NZ623068B2 - Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases - Google Patents
Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases Download PDFInfo
- Publication number
- NZ623068B2 NZ623068B2 NZ623068A NZ62306812A NZ623068B2 NZ 623068 B2 NZ623068 B2 NZ 623068B2 NZ 623068 A NZ623068 A NZ 623068A NZ 62306812 A NZ62306812 A NZ 62306812A NZ 623068 B2 NZ623068 B2 NZ 623068B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- dihydroisoquinolin
- benzothiazolylcarbamoyl
- pyridinecarboxylic acid
- pyrazolyl
- methyl
- Prior art date
Links
- 201000011510 cancer Diseases 0.000 title claims description 68
- 230000006907 apoptotic process Effects 0.000 title description 14
- 206010059512 Apoptosis Diseases 0.000 title description 12
- 206010003816 Autoimmune disease Diseases 0.000 title description 3
- 206010021425 Immune system disease Diseases 0.000 title 1
- 230000001939 inductive effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 126
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 188
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 177
- 229910052739 hydrogen Inorganic materials 0.000 claims description 161
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 157
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 144
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- 239000001257 hydrogen Substances 0.000 claims description 83
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- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 75
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- WVUNYSQLFKLYNI-AATRIKPKSA-N pelitinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC1=CC=C(F)C(Cl)=C1 WVUNYSQLFKLYNI-AATRIKPKSA-N 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- NYDXNILOWQXUOF-GXKRWWSZSA-L pemetrexed disodium Chemical compound [Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 NYDXNILOWQXUOF-GXKRWWSZSA-L 0.000 description 1
- 229960003349 pemetrexed disodium Drugs 0.000 description 1
- QJVSMHJWAOSBMD-MYXYZBIASA-L pemetrexed disodium heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 QJVSMHJWAOSBMD-MYXYZBIASA-L 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 230000003285 pharmacodynamic Effects 0.000 description 1
- 230000000275 pharmacokinetic Effects 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001888 polyacrylic acid Polymers 0.000 description 1
- 230000001124 posttranscriptional Effects 0.000 description 1
- 230000001323 posttranslational Effects 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002062 proliferating Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 229940121649 protein inhibitors Drugs 0.000 description 1
- 230000003331 prothrombotic Effects 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000005494 pyridonyl group Chemical group 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 229960002185 ranimustine Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 108091006066 receptor inhibitors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000002829 reduced Effects 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000020129 regulation of cell death Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- OIRUWDYJGMHDHJ-AFXVCOSJSA-N retaspimycin hydrochloride Chemical compound Cl.N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(O)C1=CC(O)=C2NCC=C OIRUWDYJGMHDHJ-AFXVCOSJSA-N 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 229940071138 stearyl fumarate Drugs 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
- 125000004434 sulfur atoms Chemical group 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000003777 thiepinyl group Chemical group 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 125000005032 thiofuranyl group Chemical group S1C(=CC=C1)* 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical group [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- 102000002938 thrombospondin family Human genes 0.000 description 1
- 108060008245 thrombospondin family Proteins 0.000 description 1
- 229960003723 tiazofurine Drugs 0.000 description 1
- 230000030968 tissue homeostasis Effects 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 229960003181 treosulfan Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- BZLZKLMROPIZSR-UHFFFAOYSA-N triphenylsilicon Chemical group C1=CC=CC=C1[Si](C=1C=CC=CC=1)C1=CC=CC=C1 BZLZKLMROPIZSR-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical class [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000004881 tumor cells Anatomy 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229940121358 tyrosine kinase inhibitors Drugs 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-M undecanoate Chemical class CCCCCCCCCCC([O-])=O ZDPHROOEEOARMN-UHFFFAOYSA-M 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000003612 virological Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
Disclosed are compounds having Formula (I) which inhibit the activity of anti-apoptotic Bcl-xL proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-xL protein. In one embodiment, the compound of Formula (I) is 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid. iazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid.
Description
APOPTOSIS-INDUCING AGENTS FOR THE TREATMENT OF CANCER AND
IMMUNE AND AUTOIMMUNE ES
FIELD OF THE INVENTION
This invention pertains to nds which inhibit the activity of Bcl-xL
anti-apoptotic proteins, compositions containing the compounds, and methods of treating
diseases during which poptotic Bcl-xL proteins are expressed.
BACKGROUND OF THE INVENTION
Apoptosis is recognized as an essential biological s for tissue homeostasis of all
living species. In mammals in particular, it has been shown to regulate early embryonic
development. Later in life, cell death is a default mechanism by which potentially dangerous
cells (e.g., cells carrying ous defects) are removed. Several apoptotic pathways have
been red, and one of the most important involves the Bcl-2 family of proteins, which
are key regulators of the mitochondrial (also called "intrinsic") pathway of sis. See,
, N.N. and Korsmeyer, S.J. Cell (2004) 116, 205-219. The structural gy
domains BHl, BH2, BH3 and BH4 are characteristic of this family of proteins. The Bcl-2
family of proteins can be further classified into three subfamilies depending on how many of
the homology domains each protein contains and on its ical activity (i.e., whether it has
pro- or anti- apoptotic function).
The first subgroup contains proteins having all 4 homology domains, i.e., BH1, BH2,
BH3 and BH4. Their general effect is poptotic, that is to preserve a cell from starting a
cell death process. Proteins such as, for example, Bcl-2, Bcl-w, Bcl-xL, Mcl-1 and Bfl-1/A1
are members of this first subgroup. Proteins belonging to the second subgroup contain the
three homology domains BHl, BH2 and BH3, and have a pro-apoptotic effect. The two main
representative proteins of this second subgroup are Bax and Bak. Finally, the third subgroup
is composed of proteins containing only the BH3 domain and members of this subgroup are
usually referred to as "BH3-only proteins." Their biological effect on the cell is pro-
apoptotic. Bim, Bid, Bad, Bik, Noxa, Hrk, Bmf, and Puma are examples of this third
subfamily of proteins. The exact mechanism by which the Bcl-2 family proteins regulate cell
death is still not entirely known and understanding this mechanism is an active area of
research in the science community. In one hypothesis of regulation of cell death by Bcl-2
family ns, the BH3-only proteins are further categorized as either "activator" (e.g., Bim
and Bid) or "sensitizer" (e.g., Bad, Bik, Noxa, Hrk, Bmf, and Puma) proteins depending on
their regulatory function.
The key to tissue tasis is ing the delicate balance in the interactions
among the three subgroups of protein in cells. Recent studies have tried to elucidate the
mechanisms by which pro-apoptotic and anti-apoptotic ups of Bcl-2 family proteins
interact to allow a cell to undergo programmed cell death. After receiving intra- or extra-
cellular signals in cells, post-translational or transcriptional activation of BH3-only proteins
occurs. The BH3-only proteins are the primary inducers of an apoptotic e that
includes, as one step, the activation of the pro-apoptotic ns Bax and Bak on the
mitochondrial membrane in cells. Upon activation of Bax and/or Bak that are either already
anchored to the ondrial membrane or migrate to this membrane, Bax and/or Bak
oligomerize to result in mitochondrial outer membrane permeabilization (MOMP), the release
of cytochrome C, and ream activation of effector caspases, to ultimately result in cell
apoptosis. Some chers hypothesize that certain BH3-only proteins (e.g., Puma, Bim,
Bid) are "activators" in that these proteins directly engage pro-apoptotic proteins Bax and Bak
to te MOMP, while other BH3-only proteins (e.g.,Bad, Bik and Noxa) are "sensitizers"
and induce Bax and Bak oligomerization indirectly by binding anti-apoptotic proteins (e.g.,
Bcl-2, Bcl-xL, Bcl-w, Mcl-1) and displacing and "freeing-up" the ator" BH3-only
proteins, which subsequently bind to and activate pro-apoptotic proteins (e.g., Bax, Bak) to
induce cell death. Other researchers suggest that anti-apoptotic proteins engage and
seqeuester Bax and Bak directly and all BH3-only proteins regulates this interaction by
binding to anti-apoptotic proteins (e.g., Bcl-2, Bcl-xL, Bcl-w, Mcl-1) which results in the
release Bax and Bak. See, Adams, J.M. and Cory S. Oncogene (2007) 26, 1324-1337; Willis,
S.N. et al. Science (2007) 315, 856-859. Although the exact interactions through which the
anti- and pro-apoptotic Bcl-2 family proteins regulate apoptosis remain under debate, there is
a large body of scientific evidence to show that compounds which inhibit the binding of BH3-
only proteins to anti-apoptotic Bcl-2 family proteins promote apoptosis in cells.
ulated apoptotic pathways have been implicated in the pathology of many
significant diseases such as neurodegenerative conditions (up-regulated apoptosis), such as
for example, mer's disease; and proliferative diseases (down-regulated apoptosis) such
as for example, , autoimmune diseases and rombotic conditions.
In one aspect, the implication that down-regulated apoptosis (and more ularly
the Bcl-2 family of proteins) is involved in the onset of ous malignancy has revealed a
novel way of targeting this still elusive disease. Research has shown, for example, the antiapoptotic
proteins, Bcl-2 and Bcl-xL, are over-expressed in many cancer cell types. See,
Zhang J.Y., Nature Reviews/Drug Discovery, (2002) 1, 101; Kirkin, V. et al. Biochimica et
sica Acta (2004) 1644, 229-249; and Amundson, S.A. et al. Cancer Research (2000)
60, 6101-6110. The effect of this deregulation is the survival of d cells which would
otherwise have undergone apoptosis in normal conditions. The repetition of these defects
associated with unregulated proliferation is thought to be the ng point of ous
evolution. Additionally, research has shown that ly proteins can act as tumor
suppressors when expressed in diseased animals.
These findings as well as numerous others have made possible the emergence of new
strategies in drug discovery for ing cancer. If a small molecule that could mimic the
effect of BH3-only proteins were able to enter the cell and overcome the anti-apoptotic
protein over-expression, then it could be possible to reset the apoptotic process. This strategy
can have the age that it can ate the m of drug resistance which is usually a
consequence of apoptotic deregulation (abnormal survival).
Researchers also have demonstrated that platelets also contain the necessary apoptotic
machinery (e.g., Bax, Bak, Bcl-xL, Bcl-2, cytochrome c, caspase-9, caspase-3 and APAF-1)
to execute programmed cell death through the intrinsic apoptotic pathway. Although
circulating platelet production is a normal physiological process, a number of diseases are
caused or exacerbated by excess of, or undesired activation of, platelets. The above suggests
that therapeutic agents capable of inhibiting poptotic proteins in platelets and ng
the number of platelets in mammals maybe useful in treating pro-thrombotic conditions and
diseases that are characterized by an excess of, or undesired activation of, platelets.
We havedeveloped a class of small molecule BH3-only protein mimetics, i.e., ABT-
737 and ABT-263, that bind strongly to a subset of anti-apoptotic Bcl-2 proteins including
Bcl-2, Bcl-w and Bcl-xL, but only weakly to Mcl-1 and A1, and exhibits mechanism-based
cytotoxicity. These compounds were tested in animal s and demonstrated cytotoxic
ty in certain xenograft models as single agents, as well as enhanced the effects of a
number of chemotherapeutic agents on other xenograft models when used in combination.
See, Tse, C. et al. Cancer Res (2008) 68, 3421-3428; and van Delft, M.F. et al. Cancer Cell
(2006) 10, 389-399. These in vivo studies t the potential utility of inhibitors of optotic
Bcl-2 family proteins for the treatment of diseases that involve a dysregulated
apoptotic pathway.
The natural expression levels of anti-apoptotic Bcl-2 family ns members vary in
different cell types. For e, in young platelets, Bcl-xL protein is highly expressed and
plays an important role in regulating cell death (life span) of platelets. Also, in certain cancer
cell types, the cancer cell's survival is attributed to the dysregulation of the apoptotic pathway
caused by the over-expression of one or more anti-apoptotic Bcl-2 protein family members.
In view of the important role for Bcl-2 family of proteins in ting apoptosis in both
cancerous and normal (i.e., non-cancerous) cells, and the recognized inter-cell type variability
of Bcl-2 family protein expression, it is advantageous to have a small molecule tor that
selectively targets and preferably binds to one type or a subset of anti-apoptotic Bcl-2
protein(s), for example, to an anti-apoptotic Bcl-2 family member that overexpressed in a
certain cancer type. Such a selective compound also may confer certain advantages in the
clinical setting, by providing, for example, the ility to select a dosing regimen, a reduced
on-target toxic effect in normal cells, among others (e.g., lymphopenia has been observed in
Bcl-2 deficient mice). See, Nakayama, K. et al. PNAS (1994) 91, 3700-3704.
In view of the above, there is a need in the art for small molecules therapeutics that
can selectively inhibit the ty of one type or a subset of anti-apoptotic Bcl-2 proteins, for
example, of a Bcl-xL anti-apoptotic protein. The present invention fulfills at least this need.
SUMMARY OF THE INVENTION
One ment of this invention, therefore, pertains to compounds or
therapeutically acceptable salts thereof, which are useful as inhibitors of anti-apoptotic Bcl-xL
proteins, the compounds having Formula (I)
(R1)m (R2)n
N N Z1
HN O Y1 L1 Y2
(R3)p
Formula (I)
or a therapeutically acceptable salt thereof, n
X is heteroaryl; wherein the heteroaryl represented by X is optionally substituted with
one, two, three, or four R4;
Y1 is phenylene, or C5-6 heteroarylene; optionally fused to one or two rings selected
from the group consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-
1 isoptionally substituted with one,
8 heterocycloalkane, and C3-8 heterocycloalkene; wherein Y
two, three, or four substituents independently selected from the group consisting of R5, OR5,
SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2,
NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5,
NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, 2,
C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, SO2R5, C(O)NR5SO2R5,
SO2NH2, SO2NHR5, SO2N(R5)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I;
L1 is selected from the group ting of (CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-
C(O)-(CR6R7)r, )s-S-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-
(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, (CR6R7)s-NR6A-(CR6R7)r, (CR6R7)s-S(O)2NR6A-
(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r; and
Y2 is selected from the group consisting of C3-11 branched chain alkyl, C3-7 lkyl,
C4-7 cycloalkenyl, , and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl,
, and C3-7 heterocyclyl are ally fused to one or two rings selected from the group
consisting of C3-8 lkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 cycloalkene; wherein Y2 is optionally substituted with one,
two, three, four, or five substituents independently selected from the group consisting of R8,
OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, 8, OC(O)OR8, NH2, NHR8, N(R8)2,
NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8, NHC(O)OR8, NR8C(O)OR8,
NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2,
C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSO2R8, C(O)NR8SO2R8,
SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; or
L1 is a bond; and
Y2 is selected from the group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl,
and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7
heterocyclyl ented by Y2 are optionally fused to one or two rings selected from the
group consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
cycloalkane, and C3-8 heterocycloalkene; wherein each Y2 and each ring fused to Y2 are
optionally substituted with one, two, three, four, or five substituents independently selected
from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, OC(O)R8,
R8, NH2, NHR8, N(R8)2, NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8,
OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8,
NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8,
C(O)NHSO2R8, C(O)NR8SO2R8, SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN,
N3, NO2, F, Cl, Br and I;
Z1 is selected from the group consisting of C(O)OR9, 10R11, C(O)R11,
NR10C(O)R11, NR10C(O)NR10R11, OC(O)NR10R11, NR10C(O)OR9, C(=NOR10)NR10R11,
NR10C(=NCN)NR10R11, NR10S(O)2NR10R11, S(O)2R9, R10R11, N(R10)S(O)2R11,
NR10C(=NR11)NR10R11, R10R11, C(=NR10)NR10R11, n, NO2, and CN; or
Z1 is selected from the group consisting of
N O O N
O HN N O N O HN
OH N
N N
H N N
, , N , , H ,
H O O O O
N O O OH O
N S
OH Rk S OH
N O N Rk
, H Rk , , H , O ,
O O O O
OH OH O O
N N N OH N Rk
H , H , H , H ,
O Rk
O O
O O O
O S N
S N S Rk
N N Rk N
H O
H , , and H ;
R1, at each occurrence, is ndently selected from the group consisting of halo,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
R2, at each occurrence, is independently selected from the group consisting of
deuterium, halo, C1-6 alkyl, C2-6 l, C2-6 alkynyl, and C1-6 haloalkyl;
two R2 that are ed to the same carbon atom, together with said carbon atom,
ally form a ring selected from the group consisting of heterocycloalkyl,
heterocycloalkenyl, cycloalkyl, and cycloalkenyl;
R3, at each occurrence, is independently selected from the group consisting of halo,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
R4, at each occurrence, is independently selected from the group consisting of
3, OR12, CN, NO2, halogen, C(O)OR12, C(O)NR12R13,NR12C(O)R13, NR12S(O)2R14,
NR12S(O)R14, S(O)2R14, S(O)R14 and R14;
R5, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, heterocyclyl,
cycloalkyl, and cycloalkenyl;
R6A is independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, and C1-6 kyl;
R6 and R7, at each occurrence, are each independently selected from the group
ting of hydrogen, R15, OR15, SR15, S(O)R15, , C(O)R15, CO(O)R15, OC(O)R15,
OC(O)OR15, NH2, NHR15, N(R15)2, NHC(O)R15, NR15C(O)R15, NHS(O)2R15, NR15S(O)2R15,
NHC(O)OR15, NR15C(O)OR15, NHC(O)NH2, NHC(O)NHR15, NHC(O)N(R15)2,
NR15C(O)NHR15, NR15C(O)N(R15)2, C(O)NH2, C(O)NHR15, C(O)N(R15)2, C(O)NHOH,
C(O)NHOR15, C(O)NHSO2R15, C(O)NR15SO2R15, SO2NH2, SO2NHR15, 15)2,
CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I;
R8, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C2-6 l, C2-6 alkynyl, C1-6 haloalkyl, aryl, heterocyclyl, cycloalkyl, and
cycloalkenyl; wherein the R8 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl are
optionally substituted with one, two, three, four, five, or six substituents independently
selected from the group consisting of R16, OR16, SR16, 6, SO2R16, C(O)R16, CO(O)R16,
OC(O)R16, OC(O)OR16, NH2, NHR16, N(R16)2, R16, NR16C(O)R16, NHS(O)2R16,
NR16S(O)2R16, NHC(O)OR16, O)OR16, NHC(O)NH2, NHC(O)NHR16,
NHC(O)N(R16)2, NR16C(O)NHR16, NR16C(O)N(R16)2, C(O)NH2, C(O)NHR16, C(O)N(R16)2,
C(O)NHOH, OR16, C(O)NHSO2R16, C(O)NR16SO2R16, SO2NH2, SO2NHR16,
SO2N(R16)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; wherein the R8 aryl,
heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substituted with one, two, or three
substituents independently selected from the group consisting of C1-6 alkyl, C2-6 l, C2-6
alkynyl, C1-6 haloalkyl, NH2, C(O)NH2, SO2NH2, C(O)H, (O), OH, CN, NO2, OCF3,
OCF2CF3, F, Cl, Br and I;
R9 is selected from the group consisting of C1-6 alkyl, C2-6 l, C2-6 alkynyl, C1-6
kyl, cycloalkyl, phenyl and (CH2)1-4 phenyl; and
R10 and R11, at each occurrence, are each independently selected from the group
consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 haloalkyl,
phenyl and (CH2)1phenyl; or
R10 and R11, or R10 and R9, together with the atom to which each is attached are
combined to form a cyclyl;
Rk, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C2-6 l, C2-6 alkynyl, C3-7 heterocycloalkyl, C3-7 cycloalkyl and C1-6 haloalkyl;
wherein the Rk C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with aryl,
heterocyclyl, cycloalkyl, or cycloalkenyl;
R12 and R13, at each occurrence, are each independently selected from the group
consisting of hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl and (CH2)1-4
phenyl;
R14, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, C2-4 l, C2-4 alkynyl and C1-4 haloalkyl;
R12 and R13, or R12 and R14, at each occurrence, together with the atom to which each
is attached, are optionally combined to form a heterocyclyl;
R15, at each occurrence, is independently ed from the group consisting of C1-4
alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, aryl, heterocyclyl,
cycloalkyl, and cycloalkenyl; wherein the R15 C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4
haloalkyl, and C1-4 hydroxyalkyl are optionally substituted with one, two, or three substituents
independently ed from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4
haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl,
aryl, cycloalkyl, and cycloalkenyl, NH2, C(O)NH2, SO2NH2, C(O)H, C(O)OH, (O),
OH, CN, NO2, OCF3, OCF2CF3, F, Cl, Br and I;
R16, at each ence, is independently selected from the group consisting of C1-4
alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 kyl, C1-4 hydroxyalkyl, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R16 C1-4 alkyl, C2-4
alkenyl, C2-4 alkynyl, C1-4 haloalkyl, and C1-4 hydroxyalkyl are optionally substituted with one
tuent independently selected from the group consisting of OCH3, 2OCH3, and
OCH2CH2NHCH3;
q is 1, 2, or 3;
s is 0, 1, 2, or 3;
r is 0, 1, 2, or 3;
wherein the sum of s and r is 0, 1, or 2;
m is 0, 1, 2, or 3;
n is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
In another embodiment of Formula (I), Y1 is pyrrolyl, lyl, or triazolyl.
In another embodiment of Formula (I), Y1 is pyridinyl or phenyl.
In another embodiment of Formula (I), X is benzo[d]thiazolyl; which is optionally
substituted with one, two, three or four R4. In another embodiment of Formula (I), Y1 is
pyrrolyl, pyrazolyl, or triazolyl, and X is d]thiazolyl; which is optionally substituted
with one, two, three or four R4. In another embodiment of Formula (I), Y1 is pyridinyl or
phenyl, and X is benzo[d]thiazolyl; which is optionally tuted with one, two, three or
four R4.
In another embodiment of Formula (I), Y1 is pyrrolyl, pyrazolyl, or triazolyl; and Z1 is
O O O
OH N
, or H Rk .
In another embodiment of Formula (I), Y1 is
O O O
OH N
, or
pyridinyl or phenyl; and Z1 is H Rk .
In another embodiment of Formula (I), Y1 is pyrrolyl, pyrazolyl, or triazolyl;L1 is
(CR6R7)q; and Y2 is selected from the group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl,
, C5-6 heteroaryl, and C3-7 heterocycloalkyl; wherein R6 and R7, at each occurrence, are
R15 or hydrogen; and q is 1, 2, or 3. In another embodiment of Formula (I), Y1 is pyridinyl or
; L1 is (CR6R7)q; and Y2 is selected from the group consisting of C3-7 cycloalkyl, C4-7
cycloalkenyl, phenyl, C5-6 heteroaryl, and C3-7 heterocycloalkyl; wherein R6 and R7, at each
occurrence, are R15 or hydrogen; and q is 1, 2, or 3.
In another embodiment of Formula (I), Y1 is pyrrolyl, pyrazolyl, or lyl;L1 is
selected from the group consisting of (CR6R7)s-C(O)NR6A-(CR6R7)r,and (CR6R7)s-S(O)2NR6A
-(CR6R7)r; s is 0; r is 0 or 1; R6A is independently selected from the group consisting of
hydrogen, and C1-6 alkyl; and R6 and R7, at each occurrence, are hydrogen. In another
embodiment of Formula (I), Y1 is pyridinyl or phenyl; L1 is selected from the group
ting of (CR6R7)s-NR6AC(O)-(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, (CR6R7)s-NR6A-
(CR6R7)r, (CR6R7)s-S(O)2NR6A -(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r; s is 0; r is 0 or
1; R6A is independently selected from the group consisting of hydrogen, and C1-6 alkyl; and R6
and R7, at each occurrence, are hydrogen.
Still another embodiment pertains to acompound having Formula (I), selected from
the group consisting of
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
-1H-pyrazolyl)pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(pyridinylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(pyridinylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-
hydroxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(1-
phenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{4-[2-
hylamino)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
3-(1-benzyl-1H-pyrazolyl){8-[(5,6-difluoro-1,3-benzothiazolyl)carbamoyl]-
3,4-dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(4-
fluorophenyl)ethyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
benzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
3-(1-benzyl-1H-pyrazolyl){8-[(6-fluoro-1,3-benzothiazolyl)carbamoyl]-3,4-
dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid;
3-(1-benzyl-1H-pyrazolyl){8-[(6-methoxy-1,3-benzothiazolyl)carbamoyl]-
3,4-dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-3,5-dimethyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
methylbenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
methoxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-
chlorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(benzyloxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
hydroxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{3-[2-
(dimethylamino)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzylmethyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzylmethyl-1H-pyrazolyl)pyridinecarboxylic acid;
3-(1-benzyl-1H-pyrazolyl){8-[(7-chloro-1,3-benzothiazolyl)carbamoyl]-3,4-
dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[6-
(pyrrolidinyl)pyridinyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
enzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
chlorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
inylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzylcyano-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(naphthalenylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-(3-
methyl-1,2,4-oxadiazolyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
benzyl(hydroxymethyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(benzyloxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-
methyl{[6-(pyrrolidinyl)pyridinyl]methyl}-1H-pyrazolyl)pyridinecarboxylic
acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
benzyl(ethoxycarbonyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(dimethylamino)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
carboxymethyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
ybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,3-
dihydro-1H-indenyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
phenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,4-
dihydro-2H-chromenyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[2-
(dimethylamino)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
fluorobenzyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-{[3-
(dimethylamino)propyl]amino}nitrobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-
fluoronitrobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[2-
(morpholinyl)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[3-
(dimethylamino)propoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(pyridinylmethoxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[2-
(dimethylamino)ethoxy]benzyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[3-
(dimethylamino)propynyl]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,3-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,5-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,5-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,6-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
nitrobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(biphenylylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,2-
ylpropyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
cyclohexylethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(trifluoromethyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(biphenylylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclopentylmethyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
formylbenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](15-phenyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-
methyl(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-
phenylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{3-
[(dimethylamino)methyl]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(methylsulfonyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)cyclopropyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,5-
di-tert-butylbenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(morpholinylsulfonyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(4,4-
difluorocyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(trifluoromethyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(diphenylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(morpholinyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(morpholinyl)phenylpropyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(tert-butoxycarbonyl)piperidinyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-
methyl{2-[2-(morpholinyl)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(dimethylamino)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-
methyl{2-[3-(morpholinyl)propoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic
acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-
methyl[(1-methylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[2-(4-
phenyl)-4,4-dimethylcyclohexenyl]methyl}-1H-pyrazolyl)pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)ethyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
{[(1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptyl]methyl}methyl-1H-pyrazol
yl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
2R,5S)-6,6-dimethylbicyclo[3.1.1]heptyl]methyl}methyl-1H-pyrazol
yl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methylpropyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(2-
methoxyethoxy)benzyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-
[(1R,2R,4R)-bicyclo[2.2.1]heptenylmethyl]methyl-1H-pyrazolyl}pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,3-
dimethylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
methoxyphenylpropyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-
methoxyphenylbutyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
methoxyoxophenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
cyclohexylphenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(3-
methoxypropyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[3-
hydroxy(hydroxymethyl)methylpropoxy]benzyl}methyl-1H-pyrazolyl)pyridine
ylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-
methyl[2-(tetrahydro-2H-pyranylmethoxy)benzyl]-1H-pyrazolyl}pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(1,4-dioxanylmethoxy)benzyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethoxy)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](4-
phenoxyphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](3-
phenoxyphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-(4-
henoxy)phenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-(4-
chlorophenoxy)phenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](3-
benzylphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexylmethyl)methylphenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](4-
methylphenoxyphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-
methylphenoxyphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-
methylphenoxyphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-
methylphenoxyphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexylmethoxy)methylphenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][4-
(cyclohexyloxy)methylphenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexyloxy)methylphenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][4-
(cyclohexylmethoxy)methylphenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-cyano-
3-(cyclohexyloxy)phenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-chloro-
3-(cyclohexyloxy)phenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
hexylamino)methylphenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexyloxy)fluorophenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexyloxy)(trifluoromethyl)phenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-[(3,3-
dimethylcyclohexyl)oxy]methylphenyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-1H-1,2,3-triazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
benzyl(ethoxycarbonyl)methyl-1H-pyrrolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzylcarboxymethyl-1H-pyrrolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-1H-pyrrolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(4-
methylphenyl)sulfonyl]-1H-pyrrolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzoyl-1H-pyrrolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(phenylsulfonyl)-1H-pyrrolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzylcyanomethyl-1H-pyrrolyl)pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-cyano-
1-(cyclohexylmethyl)methyl-1H-pyrrolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano-
2-methyl{[1-(piperidinyl)cyclohexyl]methyl}-1H-pyrrolyl)pyridinecarboxylic
acid;
6,6'-bis[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3,3'-
bipyridine-2,2'-dicarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-
benzyl-1,2,3,4-tetrahydroisoquinolinyl)pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(piperidinylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-
(pyridinylmethyl)-1,2,3,4-tetrahydroisoquinolinyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-
(cyclohexylmethyl)-1,2,3,4-tetrahydroisoquinolinyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-
(cyclohexyloxy)-3'-methyl-3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-
(cyclohexyloxy)-3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-phenoxy-
3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-1H-pyrrolo[2,3-b]pyridinyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-
noxy-3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-
2'-[methyl(phenyl)amino]-3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(methoxymethyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3,3-
dimethyl(morpholinyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)-3,3-dimethylcyclohexyl]methyl}methyl-1H-pyrazolyl)pyridine
ylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(3-
methoxypropyl)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
N-(1,3-benzothiazolyl){5-(1-{[1-(2-methoxyethyl)cycloheptyl]methyl}
methyl-1H-pyrazolyl)[(methylsulfonyl)carbamoyl]pyridinyl}-1,2,3,4-
ydroisoquinolinecarboxamide;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
{[(1R,2R,3R,5S)(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]heptyl]methyl}-1H-
pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[1-
cyclohexyl(morpholinyl)propyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-1H-indazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-
methyl(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-
methyl({1-[3-(morpholinyl)propoxy]cycloheptyl}methyl)-1H-pyrazolyl]pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-
methyl[methyl(phenyl)amino]phenyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-
methoxy-3,3-dimethylcyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic
acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
{[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptyl]methyl}methyl-1H-1,2,3-triazol
yl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-[(3,3-
dimethylcyclohexyl)(methyl)amino]methylphenyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-
methyl{[1-(morpholinyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic
acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-
hexyl(methyl)amino]-3'-methyl-3,4'-bipyridinecarboxylic acid;
N-(1,3-benzothiazolyl)(5-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]
methyl-1H-pyrazolyl}[(methylsulfonyl)carbamoyl]pyridinyl)-1,2,3,4-
tetrahydroisoquinolinecarboxamide;
6-[8-(1,3-benzothiazolylcarbamoyl)methyl-3,4-dihydroisoquinolin-2(1H)-yl]
{5-methyl[(1-methylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-cyano-2'-
[cyclohexyl(methyl)amino]-3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-
methoxycyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-
methoxy-3,3-dimethylcyclohexyl)methyl]methyl-1H-1,2,3-triazolyl}pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({1-[2-
(1,1-dioxidothiomorpholinyl)ethoxy]cyclohexyl}methyl)methyl-1H-pyrazol
yl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano-
2-methyl{[1-(morpholinyl)cyclohexyl]methyl}-1H-pyrrolyl)pyridinecarboxylic
acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
hydroxyethoxy)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(2,3-dimethoxypropoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridine
ylic acid;
N-(1,3-benzothiazolyl){5-[5-cyano(cyclohexylmethyl)methyl-1H-pyrrol-
3-yl][(methylsulfonyl)carbamoyl]pyridinyl}-1,2,3,4-tetrahydroisoquinoline
carboxamide;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano-
1-{[1-(2-methoxyethoxy)cycloheptyl]methyl}methyl-1H-pyrrolyl)pyridinecarboxylic
acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(1,4-dioxanylmethoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-
({1-[2-(morpholinyl)oxoethoxy]cyclohexyl}methyl)-1H-pyrazol
yl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(2,3-dihydroxypropoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano-
1-{[1-(dimethylamino)cyclohexyl]methyl}methyl-1H-pyrrolyl)pyridinecarboxylic
acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-
[(cyclohexylcarbonyl)(methyl)amino]methylphenyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,3-
dimethyl[2-(methylsulfonyl)ethoxy]cyclohexyl}methyl)methyl-1H-pyrazol
yl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-
methyl{methyl[(1-methylcyclohexyl)carbonyl]amino}phenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethoxy)-3,3-dimethylcyclohexyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-cyano-
3-[(cyclohexylsulfonyl)(methyl)amino]phenyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-cyano-
3-[2-(tricyclo[3.3.1.13,7]decyl)pyrrolidinyl]phenyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-
2'-(piperidinyl)-3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(1-
exylmethoxypropyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,3-
dimethyl[2-(methylamino)ethoxy]cyclohexyl}methyl)methyl-1H-pyrazolyl]pyridine-
2-carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-
methyl[(2,6,6-trimethyltetrahydro-2H-pyranyl)methyl]-1H-pyrazolyl}pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-1H-indazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-1H-pyrrolo[2,3-c]pyridinyl)pyridinecarboxylic acid; and therapeutically
able salts, metabolites, gs, salts of metabolites, and salts of prodrugs thereof.
Another embodiment pertains to a composition for treating bladder cancer, brain
cancer, breast cancer, bone marrow cancer, al cancer, chronic lymphocytic leukemia,
colorectal , esophageal cancer, hepatocellular cancer, lymphoblastic leukemia,
follicular ma, lymphoid malignancies of T-cell or B-cell , melanoma,
myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer,
chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen
cancer, said composition comprising an excipient and a therapeutically effective amount of a
compound of Formula (I).
Another embodiment pertains to a method of ng r cancer, brain cancer,
breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal
cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular
lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous
leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic
lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer in a
patient, said method comprising stering to the patient a therapeutically effective
amount of a compound of a (I).
Another embodiment pertains to a method of treating bladder cancer, brain ,
breast cancer, bone marrow cancer, al cancer, chronic lymphocytic leukemia, colorectal
cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular
lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous
leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic
cytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer
in a patient, said method comprising administering to the patient therapeutically effective
amount of the compound of a (I) and a therapeutically effective amount of one
additional therapeutic agent or more than one additional therapeutic agent.
In an embodiment there is described herein a compound or a therapeutically
acceptable salt thereof, wherein the compound has Formula (II), Formula (III), a
(IV) or Formula (VI):
Formula (II), Formula (III),
Formula (IV), Formula (VI);
wherein
X is d]thiazolyl optionally substituted with one or two R4;
Rx, at each occurrence, is ndently ed from the group consisting of R5,
CO(O)R5, CO(O)H, CN, F, Cl, Br and I;
L1 is selected from the group consisting of (CR6R7)q, )s-C(O)-(CR6R7)r, and
(CR6R7)s-S(O)2-(CR6R7)r; and
(11396644_1):GGG
Y2 is selected from the group consisting of C3-11 branched chain alkyl, C3-7
cycloalkyl, C4-7 cycloalkenyl, , and C3-7 heterocyclyl; wherein the C3-7 lkyl,
C4-7 cycloalkenyl, phenyl, and C3-7 cyclyl are optionally fused to one benzene ring;
wherein Y2 is optionally substituted with one, two, or three tuents independently
selected from the group ting of R8, OR8, SO2R8, CO(O)R8, NHR8, N(R8)2, C(O)H,
OH, CN, NO2, F, Cl, Br and I; or
L1 is a bond; and
Y2 is selected from the group consisting of C3-7 cycloalkyl, , and C3-7
heterocyclyl; wherein the C3-7 cycloalkyl, phenyl, and C3-7 heterocyclyl represented by Y2
are optionally fused to one benzene ring; wherein each Y2 and each ring fused to Y2 are
optionally substituted with one substituent independently selected from the group
consisting of R8 and C(O)NHR8;
Z1 is selected from the group consisting of
R1 is absent;
R2, at each occurrence, is independently C1-6 alkyl;
R3 is absent;
R4, at each occurrence, is independently selected from the group consisting of OR12
and halogen;
R5, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, and cycloalkyl;
R6 and R7, at each occurrence, are each independently selected from the group
consisting of hydrogen, R15, and CO(O)R15;
R8, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C2-6 alkynyl, aryl, heterocyclyl, and cycloalkyl; wherein the R8 C1-6 alkyl, and C2-6
alkynyl are optionally tuted with one, two, or three substituents independently
selected from the group consisting of R16, OR16, SO2R16, C(O)R16, N(R16)2, OH, F, Cl, Br
and I; wherein the R8 aryl and heterocyclyl are optionally substituted with one substituent
independently selected from the group consisting of C1-6 alkyl, F, Cl, Br and I;
(11396644_1):GGG
Rk, at each occurrence, is independently C1-6 alkyl;
R12 is C1-4 alkyl;
R15, at each occurrence, is ndently selected from the group consisting of C1-4
alkyl, and aryl; wherein the R15 C1-4 alkyl is optionally substituted with one substituent
independently selected from the group consisting C1-4 alkoxy, and heterocycloalkyl;
R16, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, aryl, heterocycloalkyl, and aryl;
q is 1, 2, or 3;
s is 0;
r is 0, or 1;
m is 0;
n is 0, or 1;
o is 0, 1, or 2; and
p is 0.
In an embodiment there is described herein a composition for treating bladder cancer,
brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic cytic leukemia,
colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular
lymphoma, a lymphoid malignancy of T-cell or B-cell origin, melanoma, myelogenous leukemia,
myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung
cancer or spleen cancer, said composition comprising an excipient and a therapeutically effective
amount of the compound or therapeutically acceptable salt of the invention.
In an embodiment there is described herein use of a compound or therapeutically
acceptable salt of the invention in the manufacture of a medicament for ng bladder cancer,
brain cancer, breast cancer, bone marrow cancer, cervical cancer, c lymphocytic leukemia,
colorectal cancer, esophageal , hepatocellular , lymphoblastic leukemia, follicular
lymphoma, a lymphoid malignancy of T-cell or B-cell origin, melanoma, myelogenous leukemia,
myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung
cancer or spleen cancer.
In an embodiment there is described herein use of a nd or therapeutically
acceptable salt of the invention and one onal therapeutic agent in the manufacture of
a medicament for treating bladder cancer, brain , breast cancer, bone marrow cancer,
cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,
hepatocellular cancer, lymphoblastic ia, follicular lymphoma, a lymphoid
malignancy of T-cell or B-cell origin, ma, enous ia,
(11396644_1):GGG
myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small
cell lung cancer or spleen cancer.
In an embodiment there is described herein 6-[8-(1,3-Benzothiazolylcarbamoyl)-
3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]
methyl-1H-pyrazolyl}pyridinecarboxylic acid or a therapeutically able salt
thereof.
In an embodiment there is described herein a ition comprising a
pharmaceutically able excipient and a eutically effective amount of 6-[8-(1,3-
benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-methoxy-3,3-
dimethylcyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid or a
therapeutically acceptable salt thereof.
In an ment there is bed herein use of 6-[8-(1,3-benzothiazol
ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-methoxy-3,3-
dimethylcyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid or a
therapeutically acceptable salt thereof in the manufacture of a medicament for treating
bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic
lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer,
lymphoblastic ia, follicular ma, a lymphoid malignancy of T-cell or B-cell
origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer,
non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen cancer.
In an embodiment there is described herein a method of treating bladder cancer, brain
cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia,
colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular
ma, a lymphoid malignancy of T-cell or B-cell origin, melanoma, myelogenous leukemia,
myeloma, oral , ovarian cancer, non-small cell lung cancer, te cancer, small cell lung
cancer or spleen cancer in a non-human patient, the method comprising administering to the patient
a therapeutically effective amount of a compound or therapeutically acceptable salt of the
invention.
(11396644_1):GGG
DETAILED DESCRIPTION OF THE INVENTION
iations and Definitions
Unless otherwise defined herein, scientific and cal terms used in connection
with the present invention shall have the meanings that are commonly understood by those
of ordinary skill in the art. The meaning and scope of the terms should be clear, however,
in the event of any latent ambiguity, definitions provided herein take ent over any
dictionary or extrinsic definition. In this application, the use of "or" means "and/or" unless
stated otherwise. Furthermore, the use of the term "including", as well as other forms, such
as "includes" and ded", is not limiting. With reference to the use of the words
"comprise" or "comprises" or "comprising" in this patent application ding the
claims), Applicants note that unless the context requires otherwise, those words are used
on the basis and clear understanding that they are to be interpreted inclusively, rather than
exclusively, and that Applicants intend each of those words to be so interpreted in
construing this patent application, including the claims below. For a variable that occurs
more than one time in any substituent or in the compound of the invention or any other
formulae herein, its definition on each occurrence is independent of its definition at every
other occurrence. Combinations of substituents are permissible only if such combinations
result in stable compounds. Stable compounds are compounds which can be isolated in a
useful degree of purity from a reaction mixture.
It is meant to be tood that proper valences are maintained for all
combinations , that monovalent moieties having more than one atom are attached
through their left ends, and that divalent moieties are drawn from left to right.
As used in the specification and the appended claims, unless specified to the
contrary, the following terms have the meaning indicated:
The term "alkyl" (alone or in combination with another )) means a straight-or
branched-chain saturated hydrocarbyl substituent typically containing from 1 to about 10
carbon atoms; or in another embodiment, from 1 to about 8 carbon atoms; in another
embodiment, from 1 to about 6 carbon atoms; and in r embodiment, from 1 to about
4 carbon atoms. Examples of such substituents include , ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, and hexyl and the like.
(11396644_1):GGG
cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular
lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous
leukemia, myeloma, oral cancer, n cancer, non-small cell lung cancer, chronic
lymphocytic leukemia, a, prostate cancer, small cell lung cancer or spleen cancer
in a patient, said method comprising administering to the patient therapeutically effective
amount of the compound of Formula (I) and a therapeutically effective amount of one
onal therapeutic agent or more than one additional therapeutic agent.
In an embodiment there is described herein a compound or a therapeutically
acceptable salt thereof, n the compound has Formula (II), Formula (III), Formula
(IV) or a (VI):
Formula (II), Formula (III),
Formula (IV), Formula (VI);
wherein
X is benzo[d]thiazolyl optionally substituted with one or two R4;
Rx, at each occurrence, is independently selected from the group ting of R5,
CO(O)R5, CO(O)H, CN, F, Cl, Br and I;
L1 is ed from the group consisting of (CR6R7)q, (CR6R7)s-C(O)-(CR6R7)r, and
(CR6R7)s-S(O)2-(CR6R7)r; and
(11396644_1):GGG
Y2 is selected from the group consisting of C3-11 branched chain alkyl, C3-7
cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl,
C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl are optionally fused to one benzene ring;
wherein Y2 is optionally substituted with one, two, or three tuents independently
ed from the group consisting of R8, OR8, SO2R8, 8, NHR8, N(R8)2, C(O)H,
OH, CN, NO2, F, Cl, Br and I; or
L1 is a bond; and
Y2 is selected from the group consisting of C3-7 cycloalkyl, phenyl, and C3-7
heterocyclyl; wherein the C3-7 cycloalkyl, phenyl, and C3-7 heterocyclyl ented by Y2
are optionally fused to one benzene ring; wherein each Y2 and each ring fused to Y2 are
optionally substituted with one substituent independently selected from the group
consisting of R8 and C(O)NHR8;
Z1 is selected from the group consisting of
R1 is absent;
R2, at each occurrence, is independently C1-6 alkyl;
R3 is absent;
R4, at each ence, is independently selected from the group consisting of OR12
and halogen;
R5, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, and cycloalkyl;
R6 and R7, at each occurrence, are each independently selected from the group
ting of hydrogen, R15, and CO(O)R15;
R8, at each occurrence, is ndently ed from the group consisting of C1-6
alkyl, C2-6 alkynyl, aryl, heterocyclyl, and cycloalkyl; wherein the R8 C1-6 alkyl, and C2-6
alkynyl are optionally substituted with one, two, or three substituents independently
selected from the group consisting of R16, OR16, SO2R16, C(O)R16, N(R16)2, OH, F, Cl, Br
and I; wherein the R8 aryl and heterocyclyl are optionally substituted with one tuent
independently selected from the group consisting of C1-6 alkyl, F, Cl, Br and I;
(11396644_1):GGG
Rk, at each occurrence, is ndently C1-6 alkyl;
R12 is C1-4 alkyl;
R15, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, and aryl; wherein the R15 C1-4 alkyl is optionally tuted with one substituent
independently ed from the group consisting C1-4 alkoxy, and heterocycloalkyl;
R16, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, aryl, heterocycloalkyl, and heteroaryl;
q is 1, 2, or 3;
s is 0;
r is 0, or 1;
m is 0;
n is 0, or 1;
o is 0, 1, or 2; and
p is 0.
In an embodiment there is described herein a composition for treating r cancer,
brain , breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia,
colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, ular
lymphoma, a lymphoid malignancy of T-cell or B-cell origin, melanoma, myelogenous leukemia,
myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung
cancer or spleen cancer, said composition comprising an excipient and a therapeutically effective
amount of the compound or therapeutically acceptable salt of the invention.
In an embodiment there is described herein use of a compound or therapeutically
acceptable salt of the invention in the manufacture of a medicament for treating bladder cancer,
brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic ia,
colorectal cancer, esophageal , hepatocellular cancer, lymphoblastic leukemia, follicular
lymphoma, a lymphoid malignancy of T-cell or B-cell origin, melanoma, myelogenous leukemia,
myeloma, oral , ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung
cancer or spleen cancer.
In an embodiment there is bed herein use of a compound or therapeutically
acceptable salt of the invention and one additional therapeutic agent in the manufacture of
a medicament for treating bladder cancer, brain cancer, breast cancer, bone marrow cancer,
cervical cancer, chronic lymphocytic ia, colorectal cancer, geal ,
hepatocellular cancer, lymphoblastic ia, follicular lymphoma, a lymphoid
malignancy of T-cell or B-cell origin, melanoma, enous leukemia,
(11396644_1):GGG
myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, te cancer, small
cell lung cancer or spleen cancer.
In an embodiment there is described herein 6-[8-(1,3-Benzothiazolylcarbamoyl)-
3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]
methyl-1H-pyrazolyl}pyridinecarboxylic acid or a therapeutically acceptable salt
thereof.
In an embodiment there is described herein a ition comprising a
pharmaceutically acceptable excipient and a therapeutically effective amount of 6-[8-(1,3-
benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-methoxy-3,3-
ylcyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid or a
therapeutically acceptable salt thereof.
In an embodiment there is described herein use of 6-[8-(1,3-benzothiazol
ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-methoxy-3,3-
dimethylcyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid or a
therapeutically acceptable salt thereof in the manufacture of a medicament for treating
bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic
lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer,
blastic leukemia, follicular lymphoma, a lymphoid malignancy of T-cell or B-cell
origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer,
non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen cancer.
In an ment there is bed herein a method of treating bladder cancer, brain
cancer, breast cancer, bone marrow cancer, cervical , chronic lymphocytic leukemia,
colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular
lymphoma, a lymphoid malignancy of T-cell or B-cell origin, melanoma, myelogenous leukemia,
myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung
cancer or spleen cancer in a man patient, the method comprising administering to the patient
a eutically effective amount of a nd or therapeutically acceptable salt of the
ion.
(11396644_1):GGG
DETAILED PTION OF THE INVENTION
Abbreviations and Definitions
Unless otherwise defined herein, scientific and technical terms used in connection
with the present invention shall have the meanings that are ly understood by those
of ordinary skill in the art. The meaning and scope of the terms should be clear, however,
in the event of any latent ambiguity, definitions provided herein take precedent over any
dictionary or extrinsic definition. In this application, the use of "or" means "and/or" unless
stated otherwise. Furthermore, the use of the term "including", as well as other forms, such
as "includes" and "included", is not limiting. With reference to the use of the words
"comprise" or "comprises" or "comprising" in this patent application (including the
claims), Applicants note that unless the context requires otherwise, those words are used
on the basis and clear understanding that they are to be interpreted inclusively, rather than
exclusively, and that Applicants intend each of those words to be so interpreted in
construing this patent ation, including the claims below. For a variable that occurs
more than one time in any substituent or in the compound of the invention or any other
formulae herein, its definition on each occurrence is independent of its definition at every
other ence. Combinations of substituents are sible only if such combinations
result in stable compounds. Stable compounds are compounds which can be isolated in a
useful degree of purity from a reaction e.
It is meant to be understood that proper valences are maintained for all
combinations herein, that monovalent moieties having more than one atom are attached
through their left ends, and that divalent moieties are drawn from left to right.
As used in the specification and the appended claims, unless specified to the
contrary, the following terms have the meaning indicated:
The term "alkyl" (alone or in combination with another term(s)) means a straight-or
branched-chain saturated hydrocarbyl substituent lly containing from 1 to about 10
carbon atoms; or in another embodiment, from 1 to about 8 carbon atoms; in r
embodiment, from 1 to about 6 carbon atoms; and in another embodiment, from 1 to about
4 carbon atoms. es of such substituents include methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, , yl, and hexyl and the like.
(11396644_1):GGG
The term "alkenyl" (alone or in combination with another term(s)) means a straightor
branched-chain hydrocarbyl substituent containing one or more double bonds and typically
from 2 to about 10 carbon atoms; or in another embodiment, from 2 to about 8 carbon atoms;
in r embodiment, from 2 to about 6 carbon atoms; and in another embodiment, from 2
to about 4 carbon atoms. Examples of such substituents include ethenyl ), 2-propenyl,
3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl and the like.
The term yl" (alone or in combination with another term(s)) means a straightor
branched-chain hydrocarbyl substituent containing one or more triple bonds and typically
from 2 to about 10 carbon atoms; or in another embodiment, from 2 to about 8 carbon atoms;
in another embodiment, from 2 to about 6 carbon atoms; and in r embodiment, from 2
to about 4 carbon atoms. Examples of such substituents include ethynyl, 2-propynyl, 3-
propynyl, 2-butynyl, and 3-butynyl and the like.
The term "carbocyclyl" (alone or in combination with another term(s)) means a
saturated cyclic (i.e., "cycloalkyl"), partially saturated cyclic (i.e., "cycloalkenyl"), or
completely rated (i.e., "aryl") hydrocarbyl substituent containing from 3 to 14 carbon
ring atoms ("ring atoms" are the atoms bound together to form the ring or rings of a cyclic
substituent). A carbocyclyl may be a single-ring (monocyclic) or polycyclic ring structure.
A carbocyclyl may be a single ring structure, which typically contains from 3 to 8
ring atoms, more typically from 3 to 6 ring atoms, and even more lly 5 to 6 ring atoms.
Examples of such single-ring carbocyclyls include cyclopropyl (cyclopropanyl), cyclobutyl
(cyclobutanyl), entyl (cyclopentanyl), cyclopentenyl, cyclopentadienyl, cyclohexyl
(cyclohexanyl), exenyl, cyclohexadienyl, cyclooxtanyl, and phenyl. A carbocyclyl
may alternatively be polycyclic (i.e., may contain more than one ring). Examples of
polycyclic carbocyclyls include bridged, fused, and spirocyclic yclyls. In a spirocyclic
carbocyclyl, one atom is common to two different rings. Examples of spirocyclic
yclyls include entanyl, spiro[3.5]nonanyl, and spiro[2.5]octanyl. In a bridged
carbocyclyl, the rings share at least two common non-adjacent atoms. Examples of d
carbocyclyls include bicyclo[2.2.1]heptanyl, o[2.2.1]heptenyl, and adamantanyl
(tricyclo[3.3.1.13,7]decanyl). In a fused-ring carbocyclyl system, two or more rings may be
fused together, such that two rings share one common bond. es of two- or three-fused
ring carbocyclyls include naphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl
(dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.
The term "cycloalkyl" (alone or in combination with another )) means a
saturated cyclic hydrocarbyl substituent containing from 3 to 14 carbon ring atoms. A
cycloalkyl may be a single carbon ring, which typically contains from 3 to 8 carbon ring
atoms and more typically from 3 to 6 ring atoms. Examples of single-ring cycloalkyls include
ropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, and cyclooctanyl. A
lkyl may alternatively be polycyclic or contain more than one ring. Examples of
polycyclic cycloalkyls include bridged, fused, and spirocyclic carbocyclyls. Examples of
bridged cycloalkyls include adamantanyl (tricyclo[3.3.1.13,7]decanyl), and
bicyclo[3.1.1]heptanyl.
The term "Cx-Cy cycloalkyl" means a cycloalkyl ring system containing from x to y
carbon atoms. For e "C3-C7 cycloalkyl" means a cycloalkyl ring system containing
from 3 to 7 carbon atoms.
The term "cycloalkenyl" (alone or in ation with another term(s)) means a
partially saturated cyclic hydrocarbyl substituent containing from 3 to 14 carbon ring atoms.
A cycloalkenyl may be a single carbon ring, which typically contains from 3 to 8 carbon ring
atoms and more typically from 4 to 6 ring atoms. Examples of single-ring cycloalkenyls
include cyclopentenyl, and cyclohexenyl. A cycloalkenyl may alternatively be polycyclic or
contain more than one ring. Examples of polycyclic cycloalkenyls e bridged, fused,
and spirocyclic carbocyclyls. Examples of bridged cycloalkenyls include bicyclo[2.2.1]hept-
2-enyl.
The term "Cx-Cy lkenyl" means a cycloalkenyl ring system ning from x
to y carbon atoms. For example "C4-C7 cycloalkenyl" means a cycloalkenyl ring system
containing from 4 to 7 carbon atoms.
The term "aryl" (alone or in combination with another term(s)) means an aromatic
yclyl containing from 6 to 14 carbon ring atoms. An aryl may be clic or
polycyclic (i.e., may n more than one ring). In the case of clic aromatic rings,
only one ring the polycyclic system is required to be unsaturated while the remaining ring(s)
may be saturated, partially saturated or unsaturated. Examples of aryls include phenyl,
naphthalenyl, indenyl, indanyl, and tetrahydronapthyl.
The term "heteroarylene" means a divalent heteroarene.
The term "arylene" means a divalent arene.
The term lene” means a divalent benzene.
In some instances, the number of carbon atoms in a substituent (e.g., alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl) is indicated by the prefix "Cx-Cy-",
wherein x is the minimum and y is the maximum number of carbon atoms. Thus, for
example, "C1-C6-alkyl"refers to an alkyl ning from 1 to 6 carbon atoms. Illustrating
further, "C3-C8-cycloalkyl" means a saturated hydrocarbyl ring containing from 3 to 8 carbon
ring atoms.
The term "Cx-y branched chain alkyl" means a saturated hydrocarbyl substituent
ning from x to y carbons wherein attachment occurs through a dialkyl trivalent- or
trialkyl tetravalent- carbon radical. Examples of such substituents include isopentanyl
(pentanyl), neopentanyl (2,2-dimethylpropanyl), yl, and 2,6-dimethylheptan
The term, "C3-11 ed chain alkyl" means a saturated hydrocarbyl substituent
containing from 3 to 11 carbons wherein attachment occurs through a l ent- or
trialkyl tetravalent- carbon radical.
The term "hydrogen" (alone or in ation with another term(s)) means a
hydrogen radical, and may be depicted as -H.
The term "hydroxy" (alone or in combination with another term(s)) means -OH.
The term "carboxy" (alone or in combination with another term(s)) means -C(O)-OH.
The term "amino" (alone or in combination with another term(s)) means -NH2.
The term "halogen" or "halo" (alone or in combination with another term(s)) means a
fluorine l (which may be depicted as -F), chlorine radical (which may be depicted as -
Cl), bromine radical (which may be depicted as -Br), or iodine radical (which may be
depicted as -I).
If a substituent is described as being "substituted", a non-hydrogen radical is in the
place of hydrogen radical on a carbon or nitrogen of the substituent. Thus, for example, a
tuted alkyl substituent is an alkyl substituent in which at least one non-hydrogen radical
is in the place of a hydrogen radical on the alkyl substituent. To illustrate, monofluoroalkyl is
alkyl substituted with a fluoro radical, and difluoroalkyl is alkyl tuted with two fluoro
radicals. It should be recognized that if there are more than one substitution on a substituent,
each non-hydrogen radical may be cal or different s otherwise stated).
If a substituent is described as being "optionally substituted", the substituent may be
either (1) not substituted or (2) substituted. If a substituent is described as being optionally
substituted with up to a particular number of non-hydrogen radicals, that substituent may be
either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen
radicals or by up to the maximum number of substitutable positions on the substituent,
whichever is less. Thus, for e, if a substituent is described as a heteroaryl optionally
substituted with up to 3 non-hydrogen radicals, then any heteroaryl with less than 3
substitutable positions would be optionally substituted by up to only as many drogen
radicals as the heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only
one substitutable position) would be ally substituted with up to one non-hydrogen
l. To illustrate further, if an amino nitrogen is described as being optionally substituted
with up to 2 non-hydrogen radicals, then a primary amino nitrogen will be optionally
substituted with up to 2 non-hydrogen radicals, whereas a secondary amino nitrogen will be
optionally substituted with up to only 1 non-hydrogen radical.
This patent application uses the terms "substituent" and "radical" interchangeably.
The prefix "halo" indicates that the substituent to which the prefix is attached is
substituted with one or more independently selected halogen radicals. For e, kyl
means an alkyl substituent in which at least one hydrogen radical is replaced with a halogen
radical. Examples of haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl. It should be recognized that if a
substituent is substituted by more than one halogen radical, those halogen radicals may be
identical or different (unless otherwise stated).
The prefix "perhalo" indicates that every hydrogen radical on the substituent to which
the prefix is attached is replaced with independently selected halogen radicals, i.e., each
hydrogen radical on the tuent is replaced with a halogen radical. If all the halogen
radicals are identical, the prefix lly will fy the halogen radical. Thus, for example,
the term "perfluoro" means that every hydrogen radical on the tuent to which the prefix
is attached is substituted with a fluorine radical. To illustrate, the term "perfluoroalkyl"
means an alkyl substituent wherein a fluorine radical is in the place of each hydrogen radical.
The term "carbonyl" (alone or in combination with r term(s)) means -C(O)-.
The term "aminocarbonyl" (alone or in combination with another term(s)) means -
C(O)-NH2.
The term "oxo" (alone or in combination with another term(s)) means (=O).
The term "oxy" (alone or in combination with another term(s)) means an ether
substituent, and may be depicted as -O-.
The term "hydroxyalkyl" (alone or in combination with another )) means –
alkyl-OH.
The term "alkylamino" (alone or in combination with another term(s)) means –alkyl-
NH2.
The term oxy" (alone or in ation with another term(s)) means an
alkylether substituent, i.e., -O-alkyl. Examples of such a substituent include methoxy (-OCH3
), ethoxy, n-propoxy, poxy, n-butoxy, toxy, sec-butoxy, and tert-butoxy.
The term "alkylcarbonyl" (alone or in combination with another )) means -
C(O)-alkyl.
The term "aminoalkylcarbonyl" (alone or in combination with another term(s)) means
alkyl-NH2.
The term "alkyloxycarbonyl" (alone or in combination with another term(s)) means -
C(O)-O-alkyl.
The term "carbocyclylcarbonyl" (alone or in combination with another term(s))
means carbocyclyl.
Similarly, the term "heterocyclylcarbonyl" (alone or in combination with another
term(s)) means -C(O)-heterocyclyl.
The term "carbocyclylalkylcarbonyl" (alone or in combination with another term(s))
means -C(O)-alkyl-carbocyclyl.
Similarly, the term "heterocyclylalkylcarbonyl" (alone or in combination with another
term(s)) means -C(O)-alkyl-heterocyclyl.
The term "carbocyclyloxycarbonyl" (alone or in combination with another term(s))
means -C(O)-O-carbocyclyl.
The term "carbocyclylalkyloxycarbonyl" (alone or in combination with another
term(s)) means -C(O)-O-alkyl-carbocyclyl.
The term "thio" or "thia" (alone or in combination with another term(s)) means
replacement by a sulfur radical, i.e. a her substituent means an ether substituent n
a divalent sulfur atom is in the place of the ether oxygen atom. Such a tuent may be
depicted as -S-. For example, "alkyl-thio-alkyl" means alkyl-S-alkyl (alkyl-sulfanyl-alkyl).
The term "thiol" or "sulfhydryl" (alone or in combination with another term(s)) means
a sulfhydryl substituent, and may be ed as -SH.
The term "(thiocarbonyl)" (alone or in combination with r term(s)) means a carbonyl
n the oxygen atom has been replaced with a sulfur. Such a substituent may be depicted
as -C(S)-.
The term "sulfonyl" (alone or in combination with another term(s)) means -S(O)2-.
The term "aminosulfonyl" (alone or in combination with another term(s)) means -
S(O)2-NH2.
The term "sulfinyl" or "sulfoxido" (alone or in combination with another term(s))
means -S(O)-.
The term ocyclyl" (alone or in combination with another term(s)) means a
saturated (i.e., "heterocycloalkyl"), partially saturated (i.e., "heterocycloalkenyl"), or
completely unsaturated (i.e., "heteroaryl") ring structure containing a total of 3 to 14 ring
atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with
the remaining ring atoms being independently ed from the group consisting of carbon,
oxygen, nitrogen, and sulfur. A heterocyclyl may be a single-ring (monocyclic) or clic
ring structure.
A cyclyl may be a single ring, which typically contains from 3 to 7 ring atoms,
more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Examples
of single-ring heterocyclyls include furanyl, dihydrofuranyl, tetrahydrofuranyl,
tetrahydropyranyl, thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl,
pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl,
pyrazolinyl, lidinyl, triazolyl, olyl, oxazolyl, oxazolidinyl, isoxazolidinyl,
isoxazolyl, thiazolyl, azolyl, thiazolinyl, azolinyl, thiazolidinyl, isothiazolidinyl,
thiodiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl
(furazanyl), or 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl or 5-
oxatriazolyl), dioxazolyl (including dioxazolyl, 1,2,4-dioxazolyl, dioxazolyl, or
1,3,4-dioxazolyl), oxanyl, hiomorpholinyl, oxathiazolyl, oxathiolyl, oxathiolanyl,
pyranyl, opyranyl, thiopyranyl, tetrahydrothiopyranyl, pyridinyl l), piperidinyl,
diazinyl (including pyridazinyl (1,2-diazinyl), pyrimidinyl (1,3-diazinyl), or pyrazinyl (1,4-
diazinyl)), piperazinyl, triazinyl (including 1,3,5-triazinyl, 1,2,4-triazinyl, and 1,2,3-
triazinyl)), oxazinyl (including 1,2-oxazinyl, 1,3-oxazinyl, or 1,4-oxazinyl)), oxathiazinyl
(including oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl, or 1,2,6-oxathiazinyl)),
zinyl (including 1,2,3-oxadiazinyl, oxadiazinyl, 1,4,2-oxadiazinyl, or 1,3,5-
oxadiazinyl)), morpholinyl, azepinyl, oxepinyl, thiepinyl, diazepinyl, pyridonyl (including
pyrid-2(1H)-onyl and pyrid-4(1H)-onyl), furan-2(5H)-onyl, pyrimidonyl ding pyramid-
2(1H)-onyl and d-4(3H)-onyl), oxazol-2(3H)-onyl, 1H-imidazol-2(3H)-onyl,
pyridazin-3(2H)-onyl, and pyrazin-2(1H)-onyl.
A cyclyl may alternatively be polycyclic (i.e., may contain more than one ring).
Examples of polycyclic heterocyclyls include bridged, fused, and spirocyclic heterocyclyls.
In a spirocyclic heterocyclyl, one atom is common to two different rings. In a d
heterocyclyl, the rings share at least two common non-adjacent atoms. Examples of bridged
heterocyclyls include 2-oxatricyclo[3.3.1.13,7]decane. In a fused-ring heterocyclyl, two or
more rings may be fused together, such that two rings share one common bond. Examples of
fused ring heterocyclyls containing two or three rings e opyrazinyl (including
imidazo[1,2-a]pyrazinyl), imidazopyridinyl (including imidazo[1,2-a]pyridinyl),
imidazopyridazinyl (including imidazo[1,2-b]pyridazinyl), thiazolopyridinyl (including
thiazolo[5,4-c]pyridinyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-b]pyridinyl, and thiazolo[4,5-
c]pyridinyl), indolizinyl, pyranopyrrolyl, 4H-quinolizinyl, l, naphthyridinyl,
pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-
pyridinyl), and pteridinyl. Other examples of fused-ring heterocyclyls include benzo-fused
heterocyclyls, such as dihydrochromenyl, tetrahydroisoquinolinyl, indolyl, isoindolyl
(isobenzazolyl, pseudoisoindolyl), indoleninyl (pseudoindolyl), isoindazolyl (benzpyrazolyl),
benzazinyl (including quinolinyl (1-benzazinyl) or isoquinolinyl (2-benzazinyl)),
phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (1,2-
benzodiazinyl) or quinazolinyl (1,3-benzodiazinyl)), benzopyranyl (including chromanyl or
isochromanyl), benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-
benzoxazinyl, or 3,1,4-benzoxazinyl), benzo[d]thiazolyl, and benzisoxazinyl ding 1,2-
benzisoxazinyl or 1,4-benzisoxazinyl).
The term "heterocycloalkyl" (alone or in combination with another term(s)) means a
saturated heterocyclyl.
The term "Cx-Cy heterocycloalkyl" means a heterocycloalkyl ring system containing
from x to y ring atoms. For example “C3-C7 heterocycloalkyl” means a heterocycloalkyl ring
system containing 3 to 7 ring atoms.
The term "heterocycloalkenyl" (alone or in combination with another term(s)) means
a partially saturated heterocyclyl.
The term "Cx-Cy heterocycloalkenyl" means a heterocycloalkenyl ring system
containing from x to y ring atoms. For example "C3-C7 heterocycloalkenyl" means a
heterocycloalkenyl ring system containing from 3 to 7 ring atoms.
The term "heteroaryl" (alone or in combination with r term(s)) means an
aromatic heterocyclyl containing from 5 to 14 ring atoms. A heteroaryl may be a single ring
or 2 or 3 fused rings. Examples of heteroaryls e 6-membered ring tuents such as
pyridyl, l, dinyl, pyridazinyl, and 1,3,5-, 1,2,4- or 1,2,3-triazinyl; 5-membered
ring substituents such as triazolyl, pyrrolyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl,
isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-
ed fused ring substituents such as imidazopyrazinyl (including imidazo[1,2-
a]pyrazinyl) imidazopyridinyl (including imidazo[1,2-a]pyridinyl), imidazopyridazinyl
(including imidazo[1,2-b]pyridazinyl), thiazolopyridinyl (including thiazolo[5,4-c]pyridinyl,
thiazolo[5,4-b]pyridinyl, lo[4,5-b]pyridinyl, and thiazolo[4,5-c]pyridinyl),
benzo[d]thiazolyl, benzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl;
and 6/6-membered fused rings such as yranyl, quinolinyl, isoquinolinyl, cinnolinyl,
quinazolinyl, and benzoxazinyl. Heteroaryls may also be heterocyles having aromatic (4N+2
pi electron) resonance contributors such as nyl (including 2(1H)-onyl and pyrid-
4(1H)-onyl), pyrimidonyl (including pyramid-2(1H)-onyl and pyramid-4(3H)-onyl),
pyridazin-3(2H)-onyl and n-2(1H)-onyl.
The term "Cx-Cy heteroaryl" means a heteroaryl ring system containing from x to y
ring atoms. For example "C5-C6 heteroaryl" means a heteroaryl ring system containing from 5
to 6 ring atoms.
The term "heteroarylene" means a divalent heteroaryl group.
A prefix ed to a multi-component substituent only applies to the first
component. To illustrate, the term "alkylcycloalkyl" contains two components: alkyl and
cycloalkyl. Thus, the C1-C6- prefix on C1-C6-alkylcycloalkyl means that the alkyl component
of the ycloalkyl contains from 1 to 6 carbon atoms; the prefix does not describe
the cycloalkyl component. To illustrate further, the prefix "halo" on haloalkyloxyalkyl
indicates that only the alkyloxy component of the alkyloxyalkyl substituent is substituted with
one or more halogen radicals. If halogen tution may alternatively or additionally occur
on the alkyl component, the substituent would instead be described as "halogen-substituted
alkyloxyalkyl" rather than "haloalkyloxyalkyl." And finally, if the halogen substitution may
only occur on the alkyl component, the substituent would d be described as
"alkyloxyhaloalkyl."
The terms ", "treating" and "treatment" refer to a method of alleviating or
abrogating a disease and/or its attendant symptoms.
The terms "prevent", nting" and "prevention" refer to a method of preventing
the onset of a e and/or its attendant symptoms or barring a subject from acquiring a
disease. As used herein, "prevent", "preventing" and "prevention" also e delaying the
onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a
The term "therapeutically effective amount" refers to that amount of the compound
being administered sufficient to prevent development of or alleviate to some extent one or
more of the symptoms of the ion or disorder being treated.
The term "modulate" refers to the ability of a compound to increase or decrease the
function, or activity, of a kinase. ation", as used herein in its various forms, is intended
to encompass antagonism, agonism, partial antagonism and/or partial agonism of the activity
associated with kinase. Kinase inhibitors are compounds that, e.g., bind to, partially or totally
block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down
regulate signal transduction. Kinase tors are nds that, e.g., bind to, stimulate,
increase, open, te, facilitate, enhance activation, ize or up regulate signal
transduction.
The term "composition" as used herein is ed to encompass a product
comprising the specified ingredients in the specified amounts, as well as any product which
results, directly or indirectly, from combination of the specified ingredients in the specified
amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or ent must
be compatible with the other ingredients of the formulation and not rious to the recipient
thereof.
The "subject" is defined herein to include s such as mammals, including, but
not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,
mice and the like. In preferred embodiments, the subject is a human.
The term "NH protecting group," as used herein, means trichloroethoxycarbonyl,
tribromoethoxycarbonyl, benzyloxycarbonyl, para-nitrobenzylcarbonyl,
ortho-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl,
phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl,
para-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl-oxycarbonyl,
4-(phenylazo)benzyloxycarbonyl, 2-furfuryl-oxycarbonyl, diphenylmethoxycarbonyl, 1,1-
dimethylpropoxy-carbonyl, isopropoxycarbonyl, phthaloyl, succinyl, , leucyl, 1-
adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl, triphenylmethyl, 2-
henylthio, methanesulfonyl, oluenesulfonyl, N,N-dimethylaminomethylene,
benzylidene, oxybenzylidene, 2-hydroxychlorobenzylidene, oxynaphthylmethylene
, 3-hydroxypyridylmethylene, cyclohexylidene,
2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene,
2-acetylcyclohexylidene, 3,3-dimethyloxycyclo-hexylidene, diphenylphosphoryl,
dibenzylphosphoryl, 5-methyloxo-2H-1,3-dioxolyl-methyl, hylsilyl, triethylsilyl,
and triphenylsilyl.
The term "C(O)OH protecting group," as used herein, means methyl, ethyl, n-propyl,
isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl,
triphenylmethyl, para-nitrobenzyl, para-methoxybenzyl, bis(para-methoxyphenyl)methyl,
acetylmethyl, benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl, paramethanesulfonylbenzoylmethyl
, 2-tetrahydropyranyl 2-tetrahydrofuranyl, 2,2,2-trichloroethyl
, 2-(trimethylsilyl)ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl,
phthalimidomethyl, succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, exyl,
methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl,
methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1,1-dimethylpropenyl, 3-methyl-
3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tertbutyldimethylsilyl
, tert-butyldiphenylsilyl, ylmethylsilyl, and
tert-butylmethoxyphenylsilyl.
The term "OH or SH protecting group," as used herein, means benzyloxycarbonyl, 4-
nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,
1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl,
diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-
(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-
(triphenylphosphonio)ethoxycarbonyl, uryloxycarbonyl, 1-adamantyloxycarbonyl,
vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxynaphthyloxycarbonyl,
8-quinolyloxycarbonyl, acetyl, formyl, acetyl, dichloroacetyl, trichloroacetyl,
trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl,
trichloroethyl, ethylsilylethyl, 1,1-dimethylpropenyl, 3-methylbutenyl, allyl,
benzyl (phenylmethyl), para-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl,
triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl,
methylthiomethyl, benzyloxymethyl, oxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl,
2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, para-toluenesulfonyl,
trimethylsilyl, triethylsilyl, propylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl,
utyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.
Compounds
Geometric isomers may exist in the present compounds. Compounds of this
invention may n carbon-carbon double bonds or carbon-nitrogen double bonds in the E
or Z configuration, wherein the term “E” represents higher order substituents on opposite
sides of the carbon-carbon or carbon-nitrogen double bond and the term “Z” represents higher
order substituents on the same side of the -carbon or carbon-nitrogen double bond as
determined by the Cahn-Ingold-Prelog Priority Rules. The compounds of this invention may
also exist as a e of “E” and “Z” isomers. Substituents around a cycloalkyl or
heterocycloalkyl are sometimes designated as being of cis or trans configuration.
Compounds of this invention may contain asymmetrically tuted carbon atoms in
the R or S configuration, in which the terms "R" and "S" are as defined by the IUPAC 1974
Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45,
13-10. Compounds having asymmetrically substituted carbon atoms with equal amounts of R
and S configurations are racemic at those carbon atoms. Atoms with an excess of one
configuration over the other are assigned the configuration present in the higher amount,
preferably an excess of about 85%-90%, more preferably an excess of about 95%-99%, and
still more preferably an excess greater than about 99%. Accordingly, this invention includes
racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and te
stereoisomers.
Isotope Enriched or Labeled Compounds
nds of the invention can exist in isotope-labeled or -enriched form containing
one or more atoms having an atomic mass or mass number different from the atomic mass or
mass number most ntly found in nature. Isotopes can be radioactive or non-radioactive
isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine,
and iodine include, but are not limited to, 2H, 3H, 13C, 14C, 15N, 18O, 32P, 35S, 18F, 36Cl, and 125I.
Compounds that contain other isotopes of these and/or other atoms are within the scope of
this invention.
In r embodiment, the isotope-labeled compounds contain deuterium (2H),
tritium (3H) or 14C es. Isotope-labeled compounds of this invention can be prepared by
the general methods well known to persons having ry skill in the art. Such isotopelabeled
compounds can be conveniently prepared by carrying out the procedures sed in
the Examples disclosed herein and Schemes by substituting a y available isotope-labeled
reagent for a non-labeled reagent. In some instances, compounds may be treated with
isotope-labeled reagents to exchange a normal atom with its isotope, for example, hydrogen
for deuterium can be exchanged by the action of a deuteric acid such as D2SO4/D2O. In
addition to the above, relevant ures and intermediates are disclosed, for instance, in
Lizondo, J et al., Drugs Fut, , 1116 (1996); Brickner, S J et al., J Med Chem, 39(3),
673 ; Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCT ations
WO1997010223, WO2005099353, WO1995007271, WO2006008754; US Patent Nos.
7538189; 7534814; 7531685; 1; 7521421; 7514068; 3; and US Patent
Application Publication Nos. 20090137457; 20090131485; 20090131363; 20090118238;
20090111840; 20090105338; 05307; 20090105147; 20090093422; 20090088416; and
20090082471, the methods are hereby incorporated by reference.
The isotope-labeled compounds of the invention may be used as standards to
determine the effectiveness of Bcl-xL inhibitors in binding assays. Isotope containing
compounds have been used in pharmaceutical research to investigate the in vivo metabolic
fate of the compounds by evaluation of the ism of action and metabolic pathway of
the nonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)).
Such lic studies are important in the design of safe, effective therapeutic drugs, either
because the in vivo active compound administered to the patient or because the metabolites
produced from the parent compound prove to be toxic or carcinogenic (Foster et al., Advances
in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al., J. Labelled
Comp. Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J. Physiol.
Pharmacol., 77, 79-88 (1999).
In on, non-radio active isotope containing drugs, such as deuterated drugs called
“heavy drugs,” can be used for the treatment of diseases and conditions d to Bcl-xL
activity. Increasing the amount of an e present in a compound above its l
abundance is called enrichment. Examples of the amount of enrichment include from about
0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79,
84, 88, 92, 96, to about 100 mol %. Replacement of up to about 15% of normal atom with a
heavy e has been ed and maintained for a period of days to weeks in mammals,
including rodents and dogs, with minimal observed adverse effects (Czajka D M and Finkel A
J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F, Ann. New York Acad. Sci 1960 84: 736;
Czakja D M et al., Am. J. Physiol. 1961 201: 357). Acute replacement of as high as 15%-
23% in human fluids with deuterium was found not to cause toxicity (Blagojevic N et al. in
"Dosimetry & Treatment Planning for Neutron e Therapy", Zamenhof R, Solares G
and Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp.125-134; Diabetes
Metab. 23: 251 (1997)).
Stable e labeling of a drug can alter its physico-chemical properties such as pKa
and lipid solubility. These effects and alterations can affect the pharmacodynamic response
of the drug molecule if the isotopic substitution affects a region involved in a ligand-receptor
interaction. While some of the physical properties of a stable isotope-labeled molecule are
different from those of the unlabeled one, the chemical and biological properties are the same,
with one important exception: because of the increased mass of the heavy isotope, any bond
involving the heavy isotope and another atom will be stronger than the same bond between
the light e and that atom. Accordingly, the incorporation of an isotope at a site of
metabolism or enzymatic transformation will slow said reactions potentially altering the
pharmacokinetic profile or efficacy relative to the non-isotopic compound.
Suitable groups for X, Y1, L1,Y2,Z1,R1,R2,R3, m, n,and p in compounds of
Formula (I) are ndently selected. The described embodiments of the present invention
may be combined. Such combination is contemplated and within the scope of the present
invention. For example, it is contemplated that embodiments for any of X, Y1, L1, Y2, Z1, R1,
R2, R3, m, n, and p can be combined with embodiments defined for any other of X, Y1, L1, Y2,
Z1, R1, R2, R3, m, n, and p.
One embodiment of this invention, therefore, pertains to compounds or and
therapeutically able salts thereof, metabolites, prodrugs, salts of metabolites, and salts
of prodrugs thereof, which are useful as inhibitors of anti-apoptotic Bcl-xL proteins, the
compounds having Formula (I)
(R1)m (R2)n
N N Z1
HN O Y1 L1 Y2
(R3)p
X
Formula (I),
wherein
X is aryl; wherein the heteroaryl represented by X is optionally substituted with
one, two, three, or four R4;
Y1 is phenylene, or C5-6 heteroarylene; optionally fused to one or two rings selected
from the group consisting of C3-8 lkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-
1 isoptionally substituted with one,
8 heterocycloalkane, and C3-8 heterocycloalkene; wherein Y
two, three, or four substituents independently selected from the group consisting of R5, OR5,
SR5, S(O)R5, SO2R5, C(O)R5, 5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2,
NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, )OR5,
NHC(O)NH2, NHC(O)NHR5, N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2,
C(O)NHR5, C(O)N(R5)2, OH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5,
, 5, SO2N(R5)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I;
L1 is selected from the group consisting of (CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-
C(O)-(CR6R7)r, (CR6R7)s-S-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-
(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, (CR6R7)s-NR6A-(CR6R7)r, (CR6R7)s-S(O)2NR6A-
(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r; and
Y2 is selected from the group consisting of C3-11 branched chain alkyl, C3-7 lkyl,
C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl; n the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are optionally fused to one or two rings selected from the group
consisting of C3-8 cycloalkane, C3-8 cycloalkene, e, C5-6 heteroarene, C3-8
cycloalkane, and C3-8 heterocycloalkene; wherein Y2 is optionally substituted with one,
two, three, four, or five substituents ndently selected from the group consisting of R8,
OR8, SR8, S(O)R8,SO2R8, C(O)R8, CO(O)R8, OC(O)R8, OC(O)OR8, NH2, NHR8, N(R8)2,
R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8, NHC(O)OR8, NR8C(O)OR8,
NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2,
C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSO2R8, C(O)NR8SO2R8,
SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; or
L1 is a bond; and
Y2 is selected from the group consisting of C3-7 lkyl, C4-7 cycloalkenyl, ,
and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7
heterocyclyl represented by Y2 are optionally fused to one or two rings selected from the
group consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 heterocycloalkene; wherein each Y2 and each ring fused to Y2 are
optionally tuted with one, two, three, four, or five tuents independently selected
from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, 8,
OC(O)OR8, NH2, NHR8, N(R8)2, NHC(O)R8, NR8C(O)R8, 2R8, NR8S(O)2R8,
NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8,
NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8,
C(O)NHSO2R8, C(O)NR8SO2R8, SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN,
N3, NO2, F, Cl, Br and I;
Z1 is selected from the group consisting of C(O)OR9, C(O)NR10R11, C(O)R11,
NR10C(O)R11, NR10C(O)NR10R11, OC(O)NR10R11, NR10C(O)OR9, 10)NR10R11,
NR10C(=NCN)NR10R11, NR10S(O)2NR10R11, S(O)2R9, S(O)2NR10R11, N(R10)S(O)2R11,
NR10C(=NR11)NR10R11, C(=S)NR10R11, C(=NR10)NR10R11, halogen, NO2, and CN; or
Z1 is selected from the group consisting of
N O O N
O HN N O N O HN
OH N
N N
H N N
, , N , , H ,
H O O O O
N O O OH O
N S
OH Rk S OH
N O N Rk
, H Rk , , H , O ,
O O O O
OH OH O O
N N N OH N Rk
H , H , H , H ,
O Rk
O O
O O O
O S N
S N S Rk
N N Rk N
H O
H , , and H ;
R1, at each occurrence, is independently selected from the group consisting of halo,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
R2, at each occurrence, is independently ed from the group consisting of
deuterium, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 kyl;
two R2 that are attached to the same carbon atom, together with said carbon atom,
optionally form a ring selected from the group consisting of heterocycloalkyl,
heterocycloalkenyl, cycloalkyl, and cycloalkenyl;
R3, at each occurrence, is independently selected from the group consisting of halo,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
R4, at each ence, is independently selected from the group consisting of
NR12R13, OR12, CN, NO2, halogen, C(O)OR12, 12R13, NR12C(O)R13, NR12S(O)2R14,
NR12S(O)R14, 14, S(O)R14 and R14;
R5, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, heterocyclyl,
cycloalkyl, and cycloalkenyl;
R6A is independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
R6 and R7, at each occurrence, are each independently ed from the group
consisting of hydrogen, R15, OR15, SR15, S(O)R15, SO2R15, C(O)R15, 15, OC(O)R15,
OC(O)OR15, NH2, NHR15, N(R15)2, NHC(O)R15, NR15C(O)R15, NHS(O)2R15, NR15S(O)2R15,
NHC(O)OR15, NR15C(O)OR15, NHC(O)NH2, NHC(O)NHR15, N(R15)2,
NR15C(O)NHR15, NR15C(O)N(R15)2, C(O)NH2, R15, C(O)N(R15)2, C(O)NHOH,
C(O)NHOR15, C(O)NHSO2R15, C(O)NR15SO2R15, SO2NH2, SO2NHR15, SO2N(R15)2,
CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I;
R8, at each occurrence, is ndently selected from the group consisting of C1-6
alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, aryl, heterocyclyl, cycloalkyl, and
cycloalkenyl; n the R8 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl are
optionally substituted with one, two, three, four, five, or six substituents independently
selected from the group consisting of R16, OR16, SR16, S(O)R16, , C(O)R16, CO(O)R16,
OC(O)R16, OC(O)OR16, NH2, NHR16, N(R16)2, NHC(O)R16, NR16C(O)R16, NHS(O)2R16,
NR16S(O)2R16, NHC(O)OR16, NR16C(O)OR16, NHC(O)NH2, NHC(O)NHR16,
NHC(O)N(R16)2, NR16C(O)NHR16, NR16C(O)N(R16)2, C(O)NH2, R16, R16)2,
C(O)NHOH, C(O)NHOR16, SO2R16, C(O)NR16SO2R16, SO2NH2, SO2NHR16,
SO2N(R16)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; wherein the R8 aryl,
heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substituted with one, two, or three
substituents ndently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C1-6 haloalkyl, NH2, C(O)NH2, SO2NH2, C(O)H, (O), OH, CN, NO2, OCF3,
OCF2CF3, F, Cl, Br and I;
R9 is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, lkyl, phenyl and (CH2)1-4 phenyl; and
R10 and R11, at each occurrence, are each independently selected from the group
ting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 haloalkyl,
phenyl and (CH2)1phenyl; or
R10 and R11, or R10 and R9, together with the atom to which each is attached are
combined to form a heterocyclyl;
Rk, at each ence, is independently selected from the group consisting of C1-6
alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 heterocycloalkyl, C3-7 cycloalkyl and C1-6 haloalkyl;
wherein the Rk C1-6 alkyl, C2-6 l, and C2-6 alkynyl are optionally substituted with aryl,
heterocyclyl, lkyl, or cycloalkenyl;
R12 and R13, at each occurrence, are each independently selected from the group
consisting of hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl and (CH2)1-4
phenyl;
R14, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, C2-4 alkenyl, C2-4 l and C1-4 haloalkyl;
R12 and R13, or R12 and R14, at each occurrence, er with the atom to which each
is attached, are optionally ed to form a heterocyclyl;
R15, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, C2-4 l, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, aryl, heterocyclyl,
cycloalkyl, and cycloalkenyl; wherein the R15 C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4
haloalkyl, and C1-4 hydroxyalkyl are optionally substituted with one, two, or three substituents
independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4
haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl, NH2, C(O)NH2, SO2NH2, C(O)H, C(O)OH, (O),
OH, CN, NO2, OCF3, OCF2CF3, F, Cl, Br and I;
R16, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R16 C1-4 alkyl, C2-4
alkenyl, C2-4 alkynyl, C1-4 haloalkyl, and C1-4 hydroxyalkyl are optionally substituted with one
substituent independently selected from the group consisting of OCH3, OCH2CH2OCH3, and
OCH2CH2NHCH3;
q is 1, 2, or 3;
s is 0, 1, 2, or 3;
r is 0, 1, 2, or 3;
wherein the sum of s and r is 0, 1, or 2;
m is 0, 1, 2, or 3;
n is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
In one embodiment of Formula (I), m is 0, 1, 2, or 3; n is 0, 1, 2, 3, 4, 5, or 6; and p is
0, 1, or 2. In r embodiment of Formula (I), n is 0 or 1. In another embodiment of
Formula (I), n is 0 or 1; and each R2 is independently deuterium or C1-6 alkyl. In another
embodiment of Formula (I), m, n, and p are 0.
In one embodiment of Formula (I), X is heteroaryl, which is ally substituted
with one, two, three or four R4. In another embodiment of Formula (I), X is heteroaryl, which
is unsubstituted. In another embodiment of Formula (I), X is heteroaryl, which is substituted
with one R4. In another embodiment of Formula (I), X is heteroaryl, which is tuted with
two R4. In another embodiment of Formula (I), X is heteroaryl, which is substituted with one
R4, and R4 is OR12 or halogen. In another embodiment of Formula (I), X is heteroaryl, which
is substituted with two R4, and each R4 is independently OR12 or halogen. In another
embodiment of a (I), X is heteroaryl, which is substituted with one R4, and R4 is Cl, F,
or methoxy. In another embodiment of Formula (I), X is aryl, which is substituted with
two R4, and each R4 is independently F.
In one embodiment of Formula (I), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl,
lo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, lo[4,5-
b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are ally
substituted with one, two, three or four R4. In r embodiment of Formula (I), X is
benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,
thiazolo[5,4-c]pyridinyl, lo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-
b]pyridazinyl, which are unsubstituted. In another embodiment of a (I), X is
benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,
thiazolo[5,4-c]pyridinyl, lo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-
b]pyridazinyl, which are substituted with one R4. In another embodiment of Formula (I), X is
benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,
thiazolo[5,4-c]pyridinyl, lo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-
b]pyridazinyl, which are substituted with two R4. In r embodiment of Formula (I), X is
d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,
thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-
b]pyridazinyl, which are substituted with one R4, and R4 is OR12 or n. In another
embodiment of Formula (I), X is benzo[d]thiazolyl, lo[5,4-b]pyridinyl, thiazolo[4,5-
c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,
o[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are substituted with two R4, and
each R4 is independently OR12 or halogen. In another embodiment of Formula (I), X is
benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,
thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-
b]pyridazinyl, which are substituted with one R4, and R4 is Cl, F, or methoxy. In another
embodiment of Formula (I), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, lo[4,5-
c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,
imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are substituted with two R4, and
each R4 is independently F.
In one embodiment of Formula (I), X is benzo[d]thiazolyl, which is optionally
substituted with one, two, three or four R4. In another embodiment of Formula (I), X is
benzo[d]thiazolyl, which is unsubstituted. In another ment of Formula (I), X is
benzo[d]thiazolyl, which is tuted with one R4. In another embodiment of Formula (I), X
is benzo[d]thiazolyl, which is substituted with two R4. In another embodiment of Formula (I),
X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is OR12 or halogen. In
another embodiment of Formula (I), X is benzo[d]thiazolyl, which is substituted with two R4,
and each R4 is independently OR12 or halogen. In another embodiment of Formula (I), X is
benzo[d]thiazolyl, which is substituted with one R4, and R4 is Cl, F, or methoxy. In another
ment of Formula (I), X is benzo[d]thiazolyl, which is substituted with two R4, and
each R4 is ndently F.
In one embodiment of Formula (I), Z1 is selected from the group ting of
C(O)OR9, C(O)NR10R11, C(O)R11, NR10C(O)R11, NR10C(O)NR10R11, OC(O)NR10R11,
NR10C(O)OR9, C(=NOR10)NR10R11, NR10C(=NCN)NR10R11, NR10S(O)2NR10R11, S(O)2R9,
S(O)2NR10R11, N(R10)S(O)2R11, NR10C(=NR11)NR10R11, C(=S)NR10R11, C(=NR10)NR10R11,
halogen, NO2, and CN; or Z1 is selected from the group consisting of
N O O N
O HN N O N O HN
OH N
N N
H N N
, , N , , H ,
H O O O O
N O O OH O
N S
OH Rk S OH
N O N Rk
, H Rk , , H , O ,
O O O O
OH OH O O
N N N OH N Rk
H , H , H , H ,
O Rk
O O
O O O
O S N
S N S Rk
N N Rk N
H H O
H , , and .
In another ment of Formula (I), Z1 is
O O Rk
N O
HN O O
N S
N S Rk
OH N H Rk N
, , , or H O .
O O O
OH N
, or Rk .
In another ment of Formula (I), Z1 is H
In another embodiment of Formula (I), Z1 is .
In one ment of Formula (I), Y1 is phenylene, or C5-6 heteroarylene; optionally
fused to one or two rings selected from the group consisting of C3-8 cycloalkane, C3-8
cycloalkene, benzene, C5-6 heteroarene, C3-8 heterocycloalkane, and C3-8 heterocycloalkene;
wherein Y1 isoptionally substituted with one, two, three, or four substituents independently
selected from the group consisting of R5, OR5, SR5, S(O)R5, SO2R5, C(O)R5, 5,
OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2, NHC(O)R5, )R5, NHS(O)2R5,
NR5S(O)2R5, NHC(O)OR5,NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2,
NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, R5, C(O)N(R5)2, C(O)NHOH,
C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5, SO2NH2, SO2NHR5, SO2N(R5)2, CO(O)H,
C(O)H, OH, CN, N3, NO2, F, Cl, Br and I. In r embodimentof Formula (I), Y1 is
phenylene or C5-6 heteroarylene; optionally fused to one or two rings selected from the group
consisting of C5-6 heteroarene and C3-8 heterocycloalkane; wherein Y1 isoptionally substituted
with one or two substituents independently selected from the group consisting of R5,
CO(O)R5, CO(O)H, CN, F, Cl, Br and I. In another embodiment of Formula (I), Y1 is
pyrrolyl, lyl, triazolyl, nyl, or phenyl. In another embodiment of Formula (I), Y1
is pyrrolyl, pyrazolyl, or triazolyl. In another embodiment of Formula (I), Y1 is pyridinyl or
. In another embodiment of Formula (I), Y1 is pyrrolyl. In another embodiment of
Formula (I), Y1 is pyrazolyl. In another embodiment of Formula (I), Y1 is triazolyl. In
another ment of Formula (I), Y1 is pyridinyl. In another embodiment of Formula (I),
Y1 is . In another embodiment of Formula (I), Y1 is pyrrolyl, pyrazolyl, triazolyl,
pyridinyl, or ; wherein the pyrrolyl, pyrazolyl, triazolyl, pyridinyl, and phenyl
represented by Y1 are optionally substituted with one, or two substituents independently
ed from the group consisting of R5, CO(O)R5, CO(O)H, CN, F, Cl, Br and I.
In one embodiment of Formula (I), L1 is selected from the group consisting of
(CR6R7)q, (CR6R7)s-O-(CR6R7)r, )s-C(O)-(CR6R7)r, (CR6R7)s-S-(CR6R7)r, (CR6R7)s-
S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, (CR6R7)s-
NR6A-(CR6R7)r, (CR6R7)s-S(O)2NR6A-(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r;and Y2 is
selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl, C4-7
cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are ally fused to one or two rings selected from the group
consisting of C3-8 lkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 heterocycloalkene; wherein Y2 is optionally substituted with one,
two, three, four, or five substituents independently selected from the group consisting of R8,
OR8, SR8, , SO2R8, C(O)R8, CO(O)R8, OC(O)R8, OC(O)OR8, NH2, NHR8, ,
NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8, NHC(O)OR8, NR8C(O)OR8,
NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2,
R8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSO2R8, C(O)NR8SO2R8,
SO2NH2, 8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; orL1 is
a bond; and Y2 is selected from the group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl; wherein the C3-7 lkyl, C4-7 cycloalkenyl, phenyl, and C3-7
cyclylrepresented by Y2 are optionally fused to one or two rings selected from the
group consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
cycloalkane, and C3-8 heterocycloalkene; wherein each Y2 and each ring fused to Y2 are
optionally substituted with one, two, three, four, or five tuents independently selected
from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, OC(O)R8,
OC(O)OR8, NH2, NHR8, N(R8)2, NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8,
NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8,
NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8,
C(O)NHSO2R8, C(O)NR8SO2R8, SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN,
N3, NO2, F, Cl, Br and I.
In another ment of a (I), L1 is selected from the group consisting of
(CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-C(O)-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-
NR6AC(O)-(CR6R7)r, )s-NR6A-(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r;and Y2 is
selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl, C4-7
cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are optionally fused to one or two benzene rings; n Y2 is
optionally substituted with one, two, or three substituents independently selected from the
group consisting of R8, OR8, SO2R8, CO(O)R8, NHR8, N(R8)2, C(O)H, OH, CN, NO2, F, Cl,
Br and I; or L1 is a bond; and Y2 is selected from the group consisting of C3-7 lkyl,
phenyl, and C3-7 heterocyclyl; wherein the C3-7 lkyl, phenyl, and C3-7 heterocyclyl
represented by Y2 are optionally fused to one benzene ring; wherein each Y2 and each ring
fused to Y2 are ally substituted with one substituent independently selected from the
group ting of R8, C(O)NHR8, F, Cl, Br and I.
In r embodiment of Formula (I), L1 is (CR6R7)q; and Y2 is selected from the
group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7 cyclyl; wherein
R6 and R7, at each occurrence, are R15 or en; and q is 1, 2, or 3.
In another embodiment of Formula (I), L1 is selected from the group ting of
(CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-C(O)-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-
NR6AC(O)-(CR6R7)r, (CR6R7)s-NR6A-(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r;q is 1, 2,
or 3; s is 0; r is 0 or 1; R6A is independently selected from the group consisting of hydrogen,
and C1-6 alkyl; and R6 and R7, at each occurrence, are hydrogen.
In one embodiment of Formula (I), X is heteroaryl; wherein the heteroaryl
represented by X is optionally substituted with one or two R4;
Y1 is phenylene or C5-6 heteroarylene;optionally fused to one ring selected from the
group consisting of C5-6 heteroarene andC3-8 heterocycloalkane; wherein Y1 isoptionally
tuted with one or two substituents independently selected from the group consisting of
R5, CO(O)R5, CO(O)H, CN,F, Cl, Br and I;
L1 is selected from the group consisting of (CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-
C(O)-(CR6R7)r, )s-S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-(CR6R7)r, )s-NR6A-
(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r; and
Y2 is selected from the group consisting of C3-11 ed chain alkyl, C3-7 cycloalkyl,
C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are optionally fused to one benzene ring; wherein Y2 is
optionally substituted with one, two, or three substituents independently selected from the
group consisting of R8, OR8, SO2R8, CO(O)R8, NHR8, N(R8)2, C(O)H, OH, CN, NO2, F, Cl,
Br and I; or
L1 is a bond; and
Y2 is selected from the group consisting of C3-7 cycloalkyl, phenyl, and C3-7
heterocyclyl; wherein the C3-7 cycloalkyl, phenyl, and C3-7 heterocyclyl represented by Y2 are
optionally fused to one benzene ring; wherein each Y2 and each ring fused to Y2 are
optionally substituted with one substituent independently selected from the group consisting
of R8 and C(O)NHR8;
Z1 is selected from the group ting of
O O O
OH N
, and H Rk ;
R2, at each occurrence, is independently C1-6 alkyl;
R4, at each occurrence, is independently selected from the group consisting of OR12
and halogen;
R5, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, and cycloalkyl;
R6A is independently selected from the group consisting of hydrogen and C1-6 alkyl;
R6 and R7, at each occurrence, are each independently selected from the group
ting of hydrogen, R15,and CO(O)R15;
R8, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C2-6 l, aryl, heterocyclyl, and cycloalkyl; wherein the R8 C1-6 alkyl, and C2-6
alkynyl are optionally substituted with one, two, or three substituents ndently selected
from the group consisting of R16, OR16, SO2R16, C(O)R16, N(R16)2, OH, F, Cl, Br and I;
wherein the R8 aryl and heterocyclyl are optionally substituted with one substituent
independently selected from the group consisting of C1-6 alkyl, F, Cl, Br and I;
Rk, at each occurrence, is independently C1-6 alkyl;
R12 and R13, at each occurrence, are each independently C1-4 alkyl;
R15, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, and aryl; wherein the R15 C1-4 alkyl is ally tuted with one substituent
independently selected from the group consisting C1-4 alkoxy, and heterocycloalkyl;
R16, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, aryl, cycloalkyl, and heteroaryl;
q is 1, 2, or 3;
s is 0;
r is 0, or 1;
m is 0;
n is 0, or 1; and
p is 0.
Still another ment pertains to acompound having Formula (I)selected
from the group ting of
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(pyridinylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(pyridinylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-
hydroxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(1-
phenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{4-[2-
(dimethylamino)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
3-(1-benzyl-1H-pyrazolyl){8-[(5,6-difluoro-1,3-benzothiazolyl)carbamoyl]-
3,4-dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(4-
fluorophenyl)ethyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
chlorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
enzyl-1H-pyrazolyl){8-[(6-fluoro-1,3-benzothiazolyl)carbamoyl]-3,4-
dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid;
3-(1-benzyl-1H-pyrazolyl){8-[(6-methoxy-1,3-benzothiazolyl)carbamoyl]-
3,4-dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-3,5-dimethyl-1H-pyrazolyl)pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
methylbenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
methoxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-
chlorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(benzyloxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
hydroxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{3-[2-
(dimethylamino)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzylmethyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzylmethyl-1H-pyrazolyl)pyridinecarboxylic acid;
3-(1-benzyl-1H-pyrazolyl){8-[(7-chloro-1,3-benzothiazolyl)carbamoyl]-3,4-
dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[6-
(pyrrolidinyl)pyridinyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
phenyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
cyanobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
chlorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(pyridinylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzylcyano-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(naphthalenylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-(3-
methyl-1,2,4-oxadiazolyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
benzyl(hydroxymethyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(benzyloxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-
methyl{[6-(pyrrolidinyl)pyridinyl]methyl}-1H-pyrazolyl)pyridinecarboxylic
acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
benzyl(ethoxycarbonyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(dimethylamino)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzylcarboxymethyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
hydroxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,3-
dihydro-1H-indenyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
phenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,4-
dihydro-2H-chromenyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[2-
(dimethylamino)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
fluorobenzyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
hexylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-{[3-
(dimethylamino)propyl]amino}nitrobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-
fluoronitrobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[2-
(morpholinyl)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[3-
(dimethylamino)propoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(pyridinylmethoxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[2-
(dimethylamino)ethoxy]benzyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[3-
(dimethylamino)propynyl]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,3-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,5-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,5-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,6-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
nitrobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(biphenylylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,2-
dimethylpropyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
cyclohexylethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(trifluoromethyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(biphenylylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclopentylmethyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
formylbenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzylphenyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-
methyl(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-
cyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{3-
[(dimethylamino)methyl]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(methylsulfonyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)cyclopropyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,5-
di-tert-butylbenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
olinylsulfonyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(4,4-
difluorocyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(trifluoromethyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(diphenylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(morpholinyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(morpholinyl)phenylpropyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(tert-butoxycarbonyl)piperidinyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-
methyl{2-[2-(morpholinyl)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(dimethylamino)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-
methyl{2-[3-(morpholinyl)propoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic
acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-
methyl[(1-methylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[2-(4-
chlorophenyl)-4,4-dimethylcyclohexenyl]methyl}-1H-pyrazolyl)pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)ethyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
{[(1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptyl]methyl}methyl-1H-pyrazol
yl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
{[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptyl]methyl}methyl-1H-pyrazol
yl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methylpropyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(2-
methoxyethoxy)benzyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-
[(1R,2R,4R)-bicyclo[2.2.1]heptenylmethyl]methyl-1H-pyrazolyl}pyridine
ylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,3-
dimethylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
methoxyphenylpropyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-
methoxyphenylbutyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
yoxophenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
cyclohexylphenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(3-
methoxypropyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[3-
hydroxy(hydroxymethyl)methylpropoxy]benzyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-
methyl[2-(tetrahydro-2H-pyranylmethoxy)benzyl]-1H-pyrazolyl}pyridine
carboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(1,4-dioxanylmethoxy)benzyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethoxy)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](4-
phenoxyphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](3-
phenoxyphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-(4-
nitrophenoxy)phenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-(4-
chlorophenoxy)phenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](3-
benzylphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexylmethyl)methylphenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](4-
methylphenoxyphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-
methylphenoxyphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-
phenoxyphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-
methylphenoxyphenyl)pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexylmethoxy)methylphenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][4-
(cyclohexyloxy)methylphenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexyloxy)methylphenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][4-
(cyclohexylmethoxy)methylphenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-cyano-
3-(cyclohexyloxy)phenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-chloro-
3-(cyclohexyloxy)phenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexylamino)methylphenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexyloxy)fluorophenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexyloxy)(trifluoromethyl)phenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-[(3,3-
dimethylcyclohexyl)oxy]methylphenyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
-1H-1,2,3-triazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
benzyl(ethoxycarbonyl)methyl-1H-pyrrolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzylcarboxymethyl-1H-pyrrolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-1H-pyrrolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(4-
methylphenyl)sulfonyl]-1H-pyrrolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzoyl-1H-pyrrolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(phenylsulfonyl)-1H-pyrrolyl]pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzylcyanomethyl-1H-pyrrolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-cyano-
1-(cyclohexylmethyl)methyl-1H-pyrrolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano-
2-methyl{[1-(piperidinyl)cyclohexyl]methyl}-1H-pyrrolyl)pyridinecarboxylic
acid;
6,6'-bis[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3,3'-
bipyridine-2,2'-dicarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-
benzyl-1,2,3,4-tetrahydroisoquinolinyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(piperidinylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-
(pyridinylmethyl)-1,2,3,4-tetrahydroisoquinolinyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-
hexylmethyl)-1,2,3,4-tetrahydroisoquinolinyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-
(cyclohexyloxy)-3'-methyl-3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-
(cyclohexyloxy)-3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-phenoxy-
ipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-1H-pyrrolo[2,3-b]pyridinyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-
2'-phenoxy-3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-
thyl(phenyl)amino]-3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(methoxymethyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3,3-
dimethyl(morpholinyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)-3,3-dimethylcyclohexyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(3-
methoxypropyl)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
N-(1,3-benzothiazolyl){5-(1-{[1-(2-methoxyethyl)cycloheptyl]methyl}
methyl-1H-pyrazolyl)[(methylsulfonyl)carbamoyl]pyridinyl}-1,2,3,4-
ydroisoquinolinecarboxamide;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
{[(1R,2R,3R,5S)(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]heptyl]methyl}-1H-
pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[1-
cyclohexyl(morpholinyl)propyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-1H-indazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-
methyl(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-
methyl({1-[3-(morpholinyl)propoxy]cycloheptyl}methyl)-1H-pyrazolyl]pyridine
ylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-
methyl[methyl(phenyl)amino]phenyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-
methoxy-3,3-dimethylcyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic
acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
{[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptyl]methyl}methyl-1H-1,2,3-triazol
yl)pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-[(3,3-
dimethylcyclohexyl)(methyl)amino]methylphenyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-
methyl{[1-(morpholinyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic
acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-
[cyclohexyl(methyl)amino]-3'-methyl-3,4'-bipyridinecarboxylic acid;
N-(1,3-benzothiazolyl)(5-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]
methyl-1H-pyrazolyl}[(methylsulfonyl)carbamoyl]pyridinyl)-1,2,3,4-
tetrahydroisoquinolinecarboxamide;
6-[8-(1,3-benzothiazolylcarbamoyl)methyl-3,4-dihydroisoquinolin-2(1H)-yl]
{5-methyl[(1-methylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-cyano-2'-
[cyclohexyl(methyl)amino]-3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-
ycyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-
methoxy-3,3-dimethylcyclohexyl)methyl]methyl-1H-1,2,3-triazolyl}pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({1-[2-
(1,1-dioxidothiomorpholinyl)ethoxy]cyclohexyl}methyl)methyl-1H-pyrazol
yl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano-
2-methyl{[1-(morpholinyl)cyclohexyl]methyl}-1H-pyrrolyl)pyridinecarboxylic
acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
hydroxyethoxy)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(2,3-dimethoxypropoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid;
N-(1,3-benzothiazolyl){5-[5-cyano(cyclohexylmethyl)methyl-1H-pyrrol-
3-yl][(methylsulfonyl)carbamoyl]pyridinyl}-1,2,3,4-tetrahydroisoquinoline
carboxamide;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano-
(2-methoxyethoxy)cycloheptyl]methyl}methyl-1H-pyrrolyl)pyridinecarboxylic
acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(1,4-dioxanylmethoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-
methyl({1-[2-(morpholinyl)oxoethoxy]cyclohexyl}methyl)-1H-pyrazol
yl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(2,3-dihydroxypropoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano-
1-{[1-(dimethylamino)cyclohexyl]methyl}methyl-1H-pyrrolyl)pyridinecarboxylic
acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-
[(cyclohexylcarbonyl)(methyl)amino]methylphenyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,3-
dimethyl[2-(methylsulfonyl)ethoxy]cyclohexyl}methyl)methyl-1H-pyrazol
yl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-
methyl{methyl[(1-methylcyclohexyl)carbonyl]amino}phenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethoxy)-3,3-dimethylcyclohexyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-cyano-
3-[(cyclohexylsulfonyl)(methyl)amino]phenyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-cyano-
3-[2-(tricyclo[3.3.1.13,7]decyl)pyrrolidinyl]phenyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-
2'-(piperidinyl)-3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(1-
exylmethoxypropyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,3-
dimethyl[2-(methylamino)ethoxy]cyclohexyl}methyl)methyl-1H-pyrazolyl]pyridine-
2-carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-
methyl[(2,6,6-trimethyltetrahydro-2H-pyranyl)methyl]-1H-pyrazolyl}pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-1H-indazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-1H-pyrrolo[2,3-c]pyridinyl)pyridinecarboxylic acid; and therapeutically
acceptable salts, metabolites, prodrugs, salts of metabolites, and salts of gs thereof.
In another aspect, the present invention provides compounds of a (II)
(R1)m (R2)n
N N Z1
(Rx)o
HN O
(R3)p
X N
L1 Y2
(II)
and therapeutically acceptable salts, metabolites, prodrugs, salts of metabolites, and salts of
prodrugs thereof, n X, L1, Y2, Z1, R1, R2, R3, m, n, and p are as described herein for
Formula (I); Rx is as described herein for substituents on Y1, and o is 0, 1, 2, or 3.
One embodiment of this invention pertains to compounds or therapeutically
acceptable salts thereof, which are useful as inhibitors of anti-apoptotic Bcl-xL proteins, the
compounds having Formula (II)
(R1)m (R2)n
N N Z1
(Rx)o
HN O
(R3)p
X N
L1 Y2
Formula (II),
wherein
X is heteroaryl; wherein the heteroaryl represented by X is optionally tuted with
one, two, three, or four R4;
Rx,at each occurrence, is independently selected from the group consisting of R5,
OR5, SR5, S(O)R5,SO2R5, C(O)R5, 5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2,
NHC(O)R5, )R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5,
NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, )N(R5)2, C(O)NH2,
R5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5,
SO2NH2, 5, SO2N(R5)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I;
L1 is selected from the group consisting of (CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-
C(O)-(CR6R7)r, (CR6R7)s-S-(CR6R7)r, )s-S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-
(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, (CR6R7)s-NR6A-(CR6R7)r, (CR6R7)s-S(O)2NR6A-
(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r; and
Y2 is selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl,
C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are optionally fused to one or two rings selected from the group
consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 heterocycloalkene; wherein Y2 is optionally tuted with one,
two, three, four, or five substituents independently selected from the group consisting of R8,
OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, OC(O)R8, OC(O)OR8, NH2, NHR8, N(R8)2,
NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8, NHC(O)OR8, NR8C(O)OR8,
NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2,
C(O)NHR8, R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSO2R8, C(O)NR8SO2R8,
SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; or
L1 is a bond; and
Y2 is selected from the group consisting of C3-7 cycloalkyl, C4-7 lkenyl, phenyl,
and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7
heterocyclyl represented by Y2 are ally fused to one or two rings selected from the
group consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 heterocycloalkene; wherein each Y2 and each ring fused to Y2 are
optionally substituted with one, two, three, four, or five substituents independently selected
from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, C(O)R8, 8, OC(O)R8,
OC(O)OR8, NH2, NHR8, N(R8)2, NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8,
NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, )NHR8,
NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, OR8,
C(O)NHSO2R8, C(O)NR8SO2R8, SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN,
N3, NO2, F, Cl, Br and I;
Z1 is selected from the group consisting of C(O)OR9, 10R11, C(O)R11,
NR10C(O)R11, NR10C(O)NR10R11, R10R11, NR10C(O)OR9, C(=NOR10)NR10R11,
NR10C(=NCN)NR10R11, NR10S(O)2NR10R11, S(O)2R9, S(O)2NR10R11, N(R10)S(O)2R11,
NR10C(=NR11)NR10R11, C(=S)NR10R11, 0)NR10R11, halogen, NO2, and CN; or
Z1 is selected from the group consisting of
N O O N
O HN N O N O HN
OH N
N N
H N N
, , N , , H ,
H O O O O
N O O OH O
N S
OH Rk S OH
N O N Rk
, H Rk , , H , O ,
O O O O
OH OH O O
N N N OH N Rk
H , H , H , H ,
O Rk
O O
O O O
O S N
S N S Rk
N N Rk N
H O
H , , and H ;
R1, at each occurrence, is independently selected from the group consisting of halo,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 kyl;
R2, at each occurrence, is independently selected from the group ting of
deuterium, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
two R2 that are attached to the same carbon atom, together with said carbon atom,
optionally form a ring selected from the group consisting of heterocycloalkyl,
heterocycloalkenyl, cycloalkyl, and cycloalkenyl;
R3, at each occurrence, is independently selected from the group consisting of halo,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 kyl;
R4, at each occurrence, is independently selected from the group ting of
NR12R13, OR12, CN, NO2, halogen, C(O)OR12, C(O)NR12R13, NR12C(O)R13, NR12S(O)2R14,
NR12S(O)R14, S(O)2R14, S(O)R14 and R14;
R5, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, heterocyclyl,
cycloalkyl, and cycloalkenyl;
R6A is ndently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
R6 and R7, at each occurrence, are each independently selected from the group
consisting of hydrogen, R15, OR15, SR15, S(O)R15, SO2R15, C(O)R15, 15, OC(O)R15,
OC(O)OR15, NH2, NHR15, N(R15)2, R15, NR15C(O)R15, NHS(O)2R15, NR15S(O)2R15,
OR15, NR15C(O)OR15, NHC(O)NH2, NHR15, NHC(O)N(R15)2,
NR15C(O)NHR15, NR15C(O)N(R15)2, C(O)NH2, C(O)NHR15, C(O)N(R15)2, C(O)NHOH,
C(O)NHOR15, C(O)NHSO2R15, C(O)NR15SO2R15, SO2NH2, SO2NHR15, SO2N(R15)2,
, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I;
R8, at each ence, is independently selected from the group consisting of C1-6
alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, aryl, heterocyclyl, cycloalkyl, and
cycloalkenyl; wherein the R8 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl are
optionally substituted with one, two, three, four, five, or six substituents independently
ed from the group consisting of R16, OR16, SR16, S(O)R16, SO2R16, C(O)R16, CO(O)R16,
OC(O)R16, OC(O)OR16, NH2, NHR16, N(R16)2, NHC(O)R16, NR16C(O)R16, NHS(O)2R16,
NR16S(O)2R16, NHC(O)OR16, NR16C(O)OR16, NHC(O)NH2, NHC(O)NHR16,
NHC(O)N(R16)2, NR16C(O)NHR16, O)N(R16)2, C(O)NH2, C(O)NHR16, C(O)N(R16)2,
C(O)NHOH, C(O)NHOR16, C(O)NHSO2R16, C(O)NR16SO2R16, SO2NH2, SO2NHR16,
SO2N(R16)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; wherein the R8 aryl,
heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substituted with one, two, or three
substituents independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C1-6 haloalkyl, NH2, 2, , C(O)H, (O), OH, CN, NO2, OCF3,
OCF2CF3, F, Cl, Br and I;
R9 is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, cycloalkyl, phenyl and (CH2)1-4 phenyl; and
R10 and R11, at each occurrence, are each ndently selected from the group
consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 haloalkyl,
phenyl and (CH2)1phenyl; or
R10 and R11, or R10 and R9, together with the atom to which each is attached are
combined to form a heterocyclyl;
Rk, at each ence, is independently selected from the group consisting of C1-6
alkyl, C2-6 alkenyl, C2-6 l, C3-7 cycloalkyl, C3-7 lkyl and C1-6 haloalkyl;
wherein the Rk C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are ally substituted with aryl,
heterocyclyl, cycloalkyl, or cycloalkenyl;
R12 and R13, at each occurrence, are each independently selected from the group
consisting of hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl and (CH2)1-4
phenyl;
R14, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, C2-4 alkenyl, C2-4 alkynyl and C1-4 haloalkyl;
R12 and R13, or R12 and R14, at each occurrence, together with the atom to which each
is ed, are optionally combined to form a heterocyclyl;
R15, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, C2-4 alkenyl, C2-4 l, C1-4 haloalkyl, C1-4 hydroxyalkyl, aryl, heterocyclyl,
cycloalkyl, and cycloalkenyl; wherein the R15 C1-4 alkyl, C2-4 alkenyl, C2-4 l, C1-4
haloalkyl, and C1-4 hydroxyalkyl are optionally substituted with one, two, or three substituents
independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4
haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, aryl, heterocycloalkyl, cycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl, NH2, C(O)NH2, SO2NH2, C(O)H, C(O)OH, (O),
OH, CN, NO2, OCF3, OCF2CF3, F, Cl, Br and I;
R16, at each ence, is independently selected from the group consisting of C1-4
alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, lkyl, and cycloalkenyl; wherein the R16 C1-4 alkyl, C2-4
alkenyl, C2-4 alkynyl, C1-4 haloalkyl, and C1-4 hydroxyalkyl are optionally substituted with one
substituent independently selected from the group ting of OCH3, 2OCH3, and
OCH2CH2NHCH3;
q is 1, 2, or 3;
s is 0, 1, 2, or 3;
r is 0, 1, 2, or 3;
wherein the sum of s and r is 0, 1, or 2;
m is 0, 1, 2, or 3;
n is 0, 1, 2, 3, 4, 5, or 6;
o is 0, 1, 2, or 3; and
p is 0, 1, or 2.
In one embodiment of a (II), m is 0, 1, 2, or 3; n is 0, 1, 2, 3, 4, 5, or 6; and p
is 0, 1, or 2. In another embodiment of Formula (II), n is 0 or 1. In another ment of
Formula (II), n is 0 or 1; and each R2 is independently deuterium or C1-6 alkyl. In r
embodiment of Formula (II), m, n, and p are 0.
In one embodiment of Formula (II), X is heteroaryl, which is optionally substituted
with one, two, three or four R4. In another embodiment of Formula (II), X is heteroaryl,
which is unsubstituted. In another embodiment of Formula (II), X is heteroaryl, which is
substituted with one R4. In another embodiment of Formula (II), X is heteroaryl, which is
substituted with two R4. In another embodiment of Formula (II), X is heteroaryl, which is
substituted with one R4, and R4 is OR12 or halogen. In another embodiment of Formula (II), X
is heteroaryl, which is substituted with two R4, and each R4 is independently OR12 or halogen.
In another embodiment of Formula (II), X is heteroaryl, which is substituted with one R4, and
R4 is Cl, F, or y. In r embodiment of a (II), X is heteroaryl, which is
substituted with two R4, and each R4 is independently F.
In one embodiment of Formula (II), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl,
thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-
b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are optionally
tuted with one, two, three or four R4. In another embodiment of Formula (II), X is
benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,
thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-
b]pyridazinyl, which are unsubstituted. In another embodiment of Formula (II), X is
benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,
thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-
b]pyridazinyl, which are substituted with one R4. In another ment of a (II), X
is benzo[d]thiazolyl, lo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-
a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or
imidazo[1,2-b]pyridazinyl, which are substituted with two R4. In another embodiment of
Formula (II), X is benzo[d]thiazolyl, lo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,
imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-
a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are substituted with one R4, and R4 is OR12
or halogen. In another ment of Formula (II), X is benzo[d]thiazolyl, thiazolo[5,4-
b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,
thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are
substituted with two R4, and each R4 is independently OR12 or halogen. In another
embodiment of Formula (II), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-
c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,
o[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are substituted with one R4, and
R4 is Cl, F, or methoxy. In another embodiment of Formula (II), X is benzo[d]thiazolyl,
thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-
c]pyridinyl, thiazolo[4,5-b]pyridinyl, o[1,2-a]pyrazinyl, or o[1,2-b]pyridazinyl,
which are substituted with two R4, and each R4 is independently F.
In one embodiment of a (II), X is benzo[d]thiazolyl, which is optionally
substituted with one, two, three or four R4. In another ment of Formula (II), X is
benzo[d]thiazolyl, which is unsubstituted. In r embodiment of Formula (II), X is
d]thiazolyl, which is substituted with one R4. In another embodiment of Formula (II),
X is benzo[d]thiazolyl, which is substituted with two R4. In another embodiment of Formula
(II), X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is OR12 or halogen. In
another embodiment of Formula (II), X is benzo[d]thiazolyl, which is substituted with two R4,
and each R4 is independently OR12 or halogen. In another embodiment of Formula (II), X is
benzo[d]thiazolyl, which is substituted with one R4, and R4 is Cl, F, or methoxy. In another
ment of Formula (II), X is benzo[d]thiazolyl, which is substituted with two R4, and
each R4 is independently F.
In one embodiment of Formula (II), Z1 is selected from the group consisting of
C(O)OR9, C(O)NR10R11, C(O)R11, NR10C(O)R11, NR10C(O)NR10R11, OC(O)NR10R11,
O)OR9, C(=NOR10)NR10R11, NR10C(=NCN)NR10R11, NR10S(O)2NR10R11, S(O)2R9,
S(O)2NR10R11, N(R10)S(O)2R11, NR10C(=NR11)NR10R11, C(=S)NR10R11, C(=NR10)NR10R11,
halogen, NO2, and CN; or Z1 is selected from the group consisting of
N O O N
O HN N O N O HN
N OH N
N OH N
H , N N
, , , H ,
H O O O OH O O O
OH Rk N Rk S OH
N O
, H Rk , , H , O ,
O O O O
OH OH O O
N N N OH N Rk
H , H , H , H ,
O Rk
O O
O O O
O S N
S N S Rk
N N Rk N
H O
H , , and H .
In another embodiment of Formula (II), Z1 is
O O Rk
HN N O O
N S
N S Rk
OH N H Rk N
, , , or H O .
In another
O O O
OH N
, or .
ment of a (II), Z1 is H Rk
In another
OH
embodiment of Formula (II), Z1 is .
In one embodiment of Formula (II), L1 is selected from the group consisting of
(CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-C(O)-(CR6R7)r, (CR6R7)s-S-(CR6R7)r, (CR6R7)s-
S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-(CR6R7)r, )s-C(O)NR6A-(CR6R7)r, (CR6R7)s-
NR6A-(CR6R7)r, (CR6R7)s-S(O)2NR6A-(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r;and Y2 is
selected from the group consisting of C3-11 ed chain alkyl, C3-7 cycloalkyl, C4-7
cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are optionally fused to one or two rings selected from the group
consisting of C3-8 cycloalkane, C3-8 lkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 heterocycloalkene; wherein Y2 is optionally substituted with one,
two, three, four, or five substituents independently ed from the group consisting of R8,
OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, OC(O)R8, OC(O)OR8, NH2, NHR8, N(R8)2,
NHC(O)R8, )R8, NHS(O)2R8, NR8S(O)2R8, NHC(O)OR8, NR8C(O)OR8,
NHC(O)NH2, NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2,
C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSO2R8, C(O)NR8SO2R8,
SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; or L1 is
a bond; and Y2 is selected from the group consisting of C3-7 lkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7
heterocyclyl represented by Y2 are optionally fused to one or two rings selected from the
group ting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 heterocycloalkene; wherein each Y2 and each ring fused to Y2 are
optionally substituted with one, two, three, four, or five tuents independently selected
from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, , CO(O)R8, 8,
OC(O)OR8, NH2, NHR8, N(R8)2, NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8,
NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8,
NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8,
C(O)NHSO2R8, C(O)NR8SO2R8, SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN,
N3, NO2, F, Cl, Br and I.
In another embodiment of Formula (II), L1 is selected from the group consisting of
(CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-C(O)-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-
NR6AC(O)-(CR6R7)r, (CR6R7)s-NR6A-(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r;and Y2 is
selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl, C4-7
cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are optionally fused to one or two benzene rings; wherein Y2 is
optionally substituted with one, two, or three substituents independently selected from the
group consisting of R8, OR8, SO2R8, CO(O)R8, NHR8, N(R8)2, C(O)H, OH, CN, NO2, F, Cl,
Br and I; or L1 is a bond; and Y2 is selected from the group consisting of C3-7 cycloalkyl,
phenyl, and C3-7 cyclyl; n the C3-7 cycloalkyl, phenyl, and C3-7 heterocyclyl
represented by Y2 are optionally fused to one benzene ring; wherein each Y2 and each ring
fused to Y2 are optionally substituted with one substituent independently selected from the
group consisting of R8, C(O)NHR8, F, Cl, Br and I.
In another embodiment of a (II), L1 is )q; and Y2 is selected from the
group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein
R6 and R7, at each occurrence, are R15 or hydrogen; and q is 1, 2, or 3.
In another embodiment of a (II), L1 is selected from the group consisting of
(CR6R7)q, (CR6R7)s-C(O)-(CR6R7)r, and (CR6R7)s-S(O)2-(CR6R7)r; q is 1, 2, or 3; s is 0; r is 0
or 1; R6A is independently selected from the group consisting of hydrogen, and C1-6 alkyl; and
R6 and R7, at each occurrence, are hydrogen.
In one embodiment of Formula (II), o is 0. In another embodiment of Formula (II), o
is 2. In another ment of Formula (II), o is 0, 1, 2, or 3. In r embodiment of
Formula (II), ois 1, 2, or 3; and Rx, at each occurrence, is independently selected from the
group consisting of, R5, OR5, SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5,
NH2, NHR5, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5,
NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5,
NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5,
C(O)NHSO2R5, C(O)NR5SO2R5, SO2NH2, 5, SO2N(R5)2, CO(O)H, C(O)H, OH, CN,
N3, NO2, F, Cl, Br and I. In r embodiment of Formula (II), ois 1, 2, or 3; and Rx, at
each occurrence, is independently selected from the group ting of R5, CO(O)R5,
CO(O)H, CN, F, Cl, Br and I. In another embodiment of Formula (II), o is 1 or 2; Rx, at each
occurrence, is independently selected from the group consisting of R5, CO(O)R5, CO(O)H,
CN, F, Cl, Br and I; and R5, at each occurrence, is independently selected from the group
consisting of C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, and cycloalkyl.
In r embodiment of Formula (II), o is 1 or 2; Rx,at each occurrence, is independently
selected from the group consisting of R5, CN, F, Cl, Br and I; and R5, at each occurrence, is
independently selected from the group consisting of C1-2 alkyl, and C1 haloalkyl. In another
ment of Formula (II), ois 1or 2; Rx is R5 or CN; and R5 is CH3. In another
embodiment of Formula (II), ois 1; and Rx is CN.
In one ment of Formula (II), X is heteroaryl; wherein the heteroaryl
represented by X is optionally substituted with one or two R4;
Rx,at each occurrence, is independently selected from the group consisting of R5,
CO(O)R5, CO(O)H, CN, F, Cl, Br and I;
L1 is selected from the group consisting of (CR6R7)q, (CR6R7)s-C(O)-(CR6R7)r,and
(CR6R7)s-S(O)2-(CR6R7); and
Y2 is selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl,
C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl; n the C3-7 cycloalkyl, C4-7 cycloalkenyl,
, and C3-7 heterocyclyl are optionally fused to one benzene ring; wherein Y2 is
ally substituted with one, two, or three substituents independently selected from the
group consisting of R8, OR8, SO2R8, CO(O)R8, NHR8, N(R8)2, C(O)H, OH, CN, NO2, F, Cl,
Br and I; or
L1 is a bond; and
Y2 is selected from the group consisting of C3-7 lkyl, phenyl, and C3-7
heterocyclyl; wherein the C3-7 cycloalkyl, phenyl, and C3-7 heterocyclyl represented by Y2 are
ally fused to one benzene ring; wherein each Y2 and each ring fused to Y2 are
optionally substituted with one substituent independently selected from the group consisting
of R8 and C(O)NHR8;
Z1 is selected from the group consisting of
O O O
OH N
, and H Rk ;
R2, at each occurrence, is ndently C1-6 alkyl;
R4, at each occurrence, is independently selected from the group consisting of OR12
and halogen;
R5, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, and cycloalkyl;
R6A is independently selected from the group consisting of hydrogen and C1-6 alkyl;
R6 and R7, at each occurrence, are each independently selected from the group
consisting of hydrogen, R15, and CO(O)R15;
R8, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C2-6 l, aryl, heterocyclyl, and cycloalkyl; wherein the R8 C1-6 alkyl, and C2-6
alkynyl are ally substituted with one, two, or three substituents independently selected
from the group consisting of R16, OR16, SO2R16, C(O)R16, N(R16)2, OH, F, Cl, Br and I;
wherein the R8 aryl and heterocyclyl are optionally substituted with one substituent
ndently selected from the group consisting of C1-6 alkyl, F, Cl, Br and I;
Rk, at each occurrence, is independently C1-6 alkyl;
R12 and R13, at each occurrence, are each independently C1-4 alkyl;
R15, at each occurrence, is independently selected from the group ting of C1-4
alkyl, and aryl; wherein the R15 C1-4 alkyl is optionally substituted with one substituent
independently ed from the group consisting C1-4 alkoxy, and heterocycloalkyl;
R16, at each occurrence, is independently ed from the group consisting of C1-4
alkyl, aryl, cycloalkyl, and heteroaryl;
q is 1, 2, or 3;
s is 0;
r is 0, or 1;
m is 0;
n is 0, or 1;
o is 0, 1, 2, or 3; and
p is 0.
Still another embodiment pertains to a compound having Formula (II) selected from
the group consisting of
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
benzyl(ethoxycarbonyl)methyl-1H-pyrrolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
carboxymethyl-1H-pyrrolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-1H-pyrrolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(4-
methylphenyl)sulfonyl]-1H-pyrrolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzoyl-1H-pyrrolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(phenylsulfonyl)-1H-pyrrolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzylcyanomethyl-1H-pyrrolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-cyano-
1-(cyclohexylmethyl)methyl-1H-pyrrolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano-
2-methyl{[1-(piperidinyl)cyclohexyl]methyl}-1H-pyrrolyl)pyridinecarboxylic
acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-1H-pyrrolo[2,3-b]pyridinyl)pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano-
2-methyl{[1-(morpholinyl)cyclohexyl]methyl}-1H-pyrrolyl)pyridinecarboxylic
acid;
N-(1,3-benzothiazolyl){5-[5-cyano(cyclohexylmethyl)methyl-1H-pyrrol-
3-yl][(methylsulfonyl)carbamoyl]pyridinyl}-1,2,3,4-tetrahydroisoquinoline
carboxamide;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano-
1-{[1-(2-methoxyethoxy)cycloheptyl]methyl}methyl-1H-pyrrolyl)pyridinecarboxylic
acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano-
(dimethylamino)cyclohexyl]methyl}methyl-1H-pyrrolyl)pyridinecarboxylic
acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](11H-pyrrolo[2,3-c]pyridinyl)pyridinecarboxylic acid; and eutically
acceptable salts, metabolites, prodrugs, salts of metabolites, and salts of prodrugs thereof.
In another aspect, the present invention provides compounds of Formula (III)
(R1)m (R2)n
N N Z1
(Rx)o
HN O
(R3)p N
X N
L1 Y2
(III)
and therapeutically acceptable salts, metabolites, prodrugs, salts of metabolites, and salts of
prodrugs thereof, wherein X, L1, Y2, Z1, R1, R2, R3, m, n, and p are as described herein for
Formula (I); Rx is as described herein for substituents on Y1, and o is 0, 1, or 2.
One embodiment of this ion pertains to compounds or therapeutically
acceptable salts thereof, which are useful as inhibitors of anti-apoptotic Bcl-xL proteins, the
nds having Formula (III)
(R1)m (R2)n
N N Z1
(Rx)o
HN O
(R3)p N
X N
L1 Y2
Formula (III),
wherein
X is heteroaryl; wherein the heteroaryl represented by X is optionally substituted with
one, two, three, or four R4;
Rx,at eachoccurrence, is ndently selected from the group consisting of R5,
OR5, SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, 5, OC(O)OR5, NH2, NHR5, N(R5)2,
NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, )OR5,
NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2,NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2,
C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5,
SO2NH2, SO2NHR5, SO2N(R5)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I;
L1 is selected from the group consisting of (CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-
C(O)-(CR6R7)r, (CR6R7)s-S-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-
)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, (CR6R7)s-NR6A-(CR6R7)r, (CR6R7)s-S(O)2NR6A-
(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r; and
Y2 is selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl,
C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are optionally fused to one or two rings selected from the group
consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 heterocycloalkene; wherein Y2 is optionally substituted with one,
two, three, four, or five substituents independently ed from the group consisting of R8,
OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, OC(O)R8, OC(O)OR8, NH2, NHR8, N(R8)2,
NHC(O)R8, )R8, 2R8, )2R8, NHC(O)OR8, NR8C(O)OR8,
NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, )NHR8, NR8C(O)N(R8)2, C(O)NH2,
C(O)NHR8, R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSO2R8, C(O)NR8SO2R8,
SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; or
L1 is a bond; and
Y2 is selected from the group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl,
and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7
heterocyclyl ented by Y2 are ally fused to one or two rings selected from the
group consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 heterocycloalkene; n each Y2 and each ring fused to Y2 are
optionally substituted with one, two, three, four, or five substituents independently selected
from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, OC(O)R8,
R8, NH2, NHR8, , NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8,
NHC(O)OR8, NR8C(O)OR8, NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8,
NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8,
C(O)NHSO2R8, C(O)NR8SO2R8, SO2NH2, SO2NHR8, 8)2, CO(O)H, C(O)H, OH, CN,
N3, NO2, F, Cl, Br and I;
Z1 is selected from the group consisting of C(O)OR9, C(O)NR10R11, C(O)R11,
NR10C(O)R11, NR10C(O)NR10R11, R10R11, NR10C(O)OR9, C(=NOR10)NR10R11,
NR10C(=NCN)NR10R11, NR10S(O)2NR10R11, S(O)2R9, S(O)2NR10R11, N(R10)S(O)2R11,
NR10C(=NR11)NR10R11, C(=S)NR10R11, C(=NR10)NR10R11, halogen, NO2, and CN; or
Z1 is selected from the group consisting of
N O O HN N
O HN N O N O N
N N OH
OH N N
H , , N , , H ,
H O O O
O O OH O O
N N S
OH Rk Rk S OH
N O N
, H Rk , , H , O ,
O O O O
OH OH O O
N N N OH N Rk
H , H , H , H ,
O Rk
O O
O O O
O S N
S N S Rk
N N Rk N
H O
H , , and H ;
R1, at each occurrence, is independently selected from the group consisting of halo,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
R2, at each occurrence, is independently selected from the group consisting of
deuterium, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
two R2 that are ed to the same carbon atom, together with said carbon atom,
optionally form a ring selected from the group consisting of heterocycloalkyl,
heterocycloalkenyl, cycloalkyl, and cycloalkenyl;
R3, at each occurrence, is independently selected from the group consisting of halo,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 kyl;
R4, at each occurrence, is independently selected from the group consisting of
NR12R13, OR12, CN, NO2, halogen, C(O)OR12, C(O)NR12R13, NR12C(O)R13, O)2R14,
NR12S(O)R14, S(O)2R14, S(O)R14 and R14;
R5, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 yalkyl, aryl, heterocyclyl,
cycloalkyl, and cycloalkenyl;
R6A is independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
R6 and R7, at each occurrence, are each independently selected from the group
ting of hydrogen, R15, OR15, SR15, S(O)R15, SO2R15, C(O)R15, CO(O)R15, OC(O)R15,
OC(O)OR15, NH2, NHR15, N(R15)2, R15, NR15C(O)R15, NHS(O)2R15, NR15S(O)2R15,
NHC(O)OR15, NR15C(O)OR15, NHC(O)NH2, NHC(O)NHR15, NHC(O)N(R15)2,
NR15C(O)NHR15, NR15C(O)N(R15)2, C(O)NH2, C(O)NHR15, C(O)N(R15)2, C(O)NHOH,
OR15, C(O)NHSO2R15, C(O)NR15SO2R15, SO2NH2, SO2NHR15, SO2N(R15)2,
CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I;
R8, at each occurrence, is ndently selected from the group consisting of C1-6
alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, aryl, heterocyclyl, cycloalkyl, and
cycloalkenyl; wherein the R8 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl are
optionally substituted with one, two, three, four, five, or six substituents independently
selected from the group consisting of R16, OR16, SR16, S(O)R16, , C(O)R16, CO(O)R16,
OC(O)R16, OC(O)OR16, NH2, NHR16, N(R16)2, NHC(O)R16, NR16C(O)R16, NHS(O)2R16,
NR16S(O)2R16, NHC(O)OR16, NR16C(O)OR16, NHC(O)NH2, NHC(O)NHR16,
NHC(O)N(R16)2, NR16C(O)NHR16, NR16C(O)N(R16)2, C(O)NH2, C(O)NHR16, C(O)N(R16)2,
OH, C(O)NHOR16, C(O)NHSO2R16, C(O)NR16SO2R16, SO2NH2, 16,
SO2N(R16)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; wherein the R8 aryl,
heterocyclyl, lkyl, and cycloalkenyl are optionally substituted with one, two, or three
substituents independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C1-6 haloalkyl, NH2, C(O)NH2, SO2NH2, C(O)H, (O), OH, CN, NO2, OCF3,
OCF2CF3, F, Cl, Br and I;
R9 is selected from the group ting of C1-6 alkyl, C2-6 alkenyl, C2-6 l, C1-6
haloalkyl, cycloalkyl, phenyl and (CH2)1-4 phenyl; and
R10 and R11, at each occurrence, are each independently selected from the group
consisting of hydrogen, C1-6 alkyl, C2-6 l, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 haloalkyl,
phenyl and (CH2)1phenyl; or
R10 and R11, or R10 and R9, together with the atom to which each is attached are
combined to form a cyclyl;
Rk, at each occurrence, is independently selected from the group ting of C1-6
alkyl, C2-6 alkenyl, C2-6 l, C3-7 heterocycloalkyl, C3-7 cycloalkyl and C1-6 haloalkyl;
wherein the Rk C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with aryl,
heterocyclyl, cycloalkyl, or cycloalkenyl;
R12 and R13, at each occurrence, are each independently selected from the group
consisting of hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 l, C1-4 haloalkyl and (CH2)1-4
phenyl;
R14, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, C2-4 alkenyl, C2-4 alkynyl and C1-4 haloalkyl;
R12 and R13, or R12 and R14, at each ence, together with the atom to which each
is attached, are optionally ed to form a heterocyclyl;
R15, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, aryl, heterocyclyl,
cycloalkyl, and cycloalkenyl; wherein the R15 C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4
haloalkyl, and C1-4 hydroxyalkyl are optionally substituted with one, two, or three substituents
independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4
haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl, NH2, C(O)NH2, SO2NH2, C(O)H, C(O)OH, (O),
OH, CN, NO2, OCF3, OCF2CF3, F, Cl, Br and I;
R16, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and lkenyl; wherein the R16 C1-4 alkyl, C2-4
l, C2-4 alkynyl, C1-4 haloalkyl, and C1-4 hydroxyalkyl are optionally tuted with one
substituent independently selected from the group consisting of OCH3, OCH2CH2OCH3, and
OCH2CH2NHCH3;
q is 1, 2, or 3;
s is 0, 1, 2, or 3;
r is 0, 1, 2, or 3;
wherein the sum of s and r is 0, 1, or 2;
m is 0, 1, 2, or 3;
n is 0, 1, 2, 3, 4, 5, or 6;
o is 0, 1, or 2; and
p is 0, 1, or 2.
In one embodiment of a (III), m is 0, 1, 2, or 3; n is 0, 1, 2, 3, 4, 5, or 6; and p
is 0, 1, or 2. In another embodiment of Formula (III), n is 0 or 1. In another embodiment of
Formula (III), n is 0 or 1; and each R2 is independently deuterium or C1-6 alkyl. In another
embodiment of Formula (III), m, n, and p are 0.
In one embodiment of Formula (III), X is heteroaryl, which is ally substituted
with one, two, three or four R4. In another embodiment of Formula (III), X is heteroaryl,
which is unsubstituted. In r ment of Formula (III), X is heteroaryl, which is
substituted with one R4. In another embodiment of a (III), X is heteroaryl, which is
substituted with two R4. In another embodiment of Formula (III), X is heteroaryl, which is
substituted with one R4, and R4 is OR12 or halogen. In another ment of Formula (III),
X is heteroaryl, which is substituted with two R4, and each R4 is ndently OR12 or
n. In another embodiment of Formula (III), X is heteroaryl, which is substituted with
one R4, and R4 is Cl, F, or methoxy. In another embodiment of Formula (III), X is heteroaryl,
which is substituted with two R4, and each R4 is independently F.
In one embodiment of a (III), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl,
thiazolo[4,5-c]pyridinyl, o[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-
b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are optionally
substituted with one, two, three or four R4. In another embodiment of Formula (III), X is
benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,
thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-
b]pyridazinyl, which are unsubstituted. In another ment of Formula (III), X is
benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,
thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-
b]pyridazinyl, which are substituted with one R4. In another embodiment of a (III), X
is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-
a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or
imidazo[1,2-b]pyridazinyl, which are substituted with two R4. In another embodiment of
Formula (III), X is benzo[d]thiazolyl, lo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,
imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-
zinyl, or imidazo[1,2-b]pyridazinyl, which are substituted with one R4, and R4 is OR12
or halogen. In another embodiment of Formula (III), X is benzo[d]thiazolyl, thiazolo[5,4-
b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,
thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are
substituted with two R4, and each R4 is independently OR12 or halogen. In another
embodiment of Formula (III), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-
c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, lo[4,5-b]pyridinyl,
imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are substituted with one R4, and
R4 is Cl, F, or methoxy. In another embodiment of Formula (III), X is benzo[d]thiazolyl,
thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-
dinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl,
which are substituted with two R4, and each R4 is independently F.
In one embodiment of a (III), X is benzo[d]thiazolyl, which is optionally
substituted with one, two, three or four R4. In another embodiment of Formula (III), X is
benzo[d]thiazolyl, which is unsubstituted. In another embodiment of a (III), X is
benzo[d]thiazolyl, which is tuted with one R4. In another embodiment of Formula (III),
X is benzo[d]thiazolyl, which is substituted with two R4. In r embodiment of Formula
(III), X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is OR12 or halogen. In
another embodiment of Formula (III), X is benzo[d]thiazolyl, which is substituted with two
R4, and each R4 is independently OR12 or halogen. In another embodiment of Formula (III),
X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is Cl, F, or methoxy. In
another embodiment of a (III), X is benzo[d]thiazolyl, which is substituted with two
R4, and each R4 is independently F.
In one ment of Formula (III), Z1 is selected from the group consisting of
C(O)OR9, C(O)NR10R11, C(O)R11, NR10C(O)R11, NR10C(O)NR10R11, OC(O)NR10R11,
NR10C(O)OR9, C(=NOR10)NR10R11, NR10C(=NCN)NR10R11, NR10S(O)2NR10R11, S(O)2R9,
S(O)2NR10R11, N(R10)S(O)2R11, NR10C(=NR11)NR10R11, C(=S)NR10R11, C(=NR10)NR10R11,
halogen, NO2, and CN; or Z1 is selected from the group consisting of
N O O HN N
O HN N O N O
OH N
N N
OH N
H N
, , N , , H ,
H O O O OH O O
O O
N N S
OH Rk
N O N Rk S OH
, H Rk , , H , O ,
O O O O
OH OH O O
N N N OH N Rk
H , H , H , H ,
O Rk
O O O O
O S N
S N S Rk
N N Rk N
H H O
H , , and .
In another embodiment of Formula (III), Z1 is
O O Rk
N O
HN O O
N S N
N S Rk
, N , H Rk N
, or O .
H In another
O O O
OH N
, or H Rk .
ment of a (III), Z1 is In another
ment of Formula (III), Z1 is .
In one embodiment of Formula (III), L1 is selected from the group consisting of
(CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-C(O)-(CR6R7)r, (CR6R7)s-S-(CR6R7)r, (CR6R7)s-
S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, (CR6R7)s-
NR6A-(CR6R7)r, (CR6R7)s-S(O)2NR6A-(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r;and Y2 is
selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl, C4-7
cycloalkenyl, phenyl, and C3-7 heterocyclyl; n the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are optionally fused to one or two rings selected from the group
consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 heterocycloalkene; wherein Y2 is optionally substituted with one,
two, three, four, or five substituents independently selected from the group consisting of R8,
OR8, SR8, S(O)R8, SO2R8, C(O)R8, 8, OC(O)R8, OC(O)OR8, NH2, NHR8, N(R8)2,
NHC(O)R8, NR8C(O)R8, 2R8, NR8S(O)2R8, NHC(O)OR8, NR8C(O)OR8,
NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, )NHR8, NR8C(O)N(R8)2, C(O)NH2,
C(O)NHR8, C(O)N(R8)2, OH, C(O)NHOR8, C(O)NHSO2R8, 8SO2R8,
SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; or L1 is
a bond; and Y2 is selected from the group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 lkenyl, phenyl, and C3-7
heterocyclyl represented by Y2 are optionally fused to one or two rings selected from the
group ting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 heterocycloalkene; wherein each Y2 and each ring fused to Y2 are
optionally tuted with one, two, three, four, or five substituents independently ed
from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, OC(O)R8,
OC(O)OR8, NH2, NHR8, N(R8)2, NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8,
NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8,
NR8C(O)N(R8)2, 2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, OR8,
C(O)NHSO2R8, C(O)NR8SO2R8, SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN,
N3, NO2, F, Cl, Br and I.
In another embodiment of Formula (III), L1 is selected from the group consisting of
(CR6R7)q, (CR6R7)s-O-(CR6R7)r, )s-C(O)-(CR6R7)r, )s-S(O)2-(CR6R7)r, (CR6R7)s-
NR6AC(O)-(CR6R7)r, (CR6R7)s-NR6A-(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r;and Y2 is
selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl, C4-7
cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are optionally fused to one or two benzene rings; wherein Y2 is
optionally substituted with one, two, or three substituents independently selected from the
group consisting of R8, OR8, SO2R8, CO(O)R8, NHR8, N(R8)2, C(O)H, OH, CN, NO2, F, Cl,
Br and I; or L1 is a bond; and Y2 is selected from the group consisting of C3-7 cycloalkyl,
phenyl, and C3-7 cyclyl; wherein the C3-7 cycloalkyl, phenyl, and C3-7 heterocyclyl
represented by Y2 are optionally fused to one benzene ring; wherein each Y2 and each ring
fused to Y2 are optionally substituted with one substituent independently selected from the
group consisting of R8, C(O)NHR8, F, Cl, Br and I.
In r embodiment of Formula (III), L1 is )q; and Y2 is selected from the
group consisting of C3-7 cycloalkyl, C4-7 lkenyl, phenyl, and C3-7 heterocyclyl; wherein
R6 and R7, at each occurrence, are R15 or hydrogen; and q is 1, 2, or 3.
In another embodiment of Formula (III), L1 is selected from the group consisting of
)q, (CR6R7)s-C(O)-(CR6R7)r, and )s-S(O)2-(CR6R7)r; q is 1, 2, or 3; s is 0; r is 0
or 1; R6A is independently selected from the group consisting of hydrogen, and C1-6 alkyl; and
R6 and R7, at each occurrence, are hydrogen.
In one embodiment of Formula (III), o is 0. In another embodiment of Formula (III),
o is 2. In another embodiment of Formula (III), o is 0, 1, or 2. In another embodiment of
Formula (III), o is 1 or 2; and Rx, at each occurrence, is independently selected from the group
consisting of, R5, OR5, SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NH2,
NHR5, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5,
)OR5, NHC(O)NH2, NHC(O)NHR5, N(R5)2, NR5C(O)NHR5,
NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5,
C(O)NHSO2R5, 5SO2R5, SO2NH2, SO2NHR5, SO2N(R5)2, CO(O)H, C(O)H, OH, CN,
N3, NO2, F, Cl, Br and I. In another embodiment of Formula (III), o is 1 or 2; and Rx, at each
occurrence, is independently selected from the group consisting of R5, CO(O)R5, CO(O)H,
CN, F, Cl, Br and I. In another embodiment of Formula (III), o is 1 or 2; Rx, at each
occurrence, is independently selected from the group consisting of R5, CO(O)R5, CO(O)H,
CN, F, Cl, Br and I; and R5, at each occurrence, is independently selected from the group
consisting of C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 yalkyl, aryl, and cycloalkyl.
In another embodiment of Formula (III), o is 1 or 2; Rx, at each occurrence, is independently
selected from the group consisting of R5, CN, F, Cl, Br and I; and R5, at each occurrence, is
independently selected from the group ting of C1-2 alkyl, and C1 haloalkyl. In another
embodiment of Formula (III), o is 1 or 2; Rx is R5 or CN; and R5 is CH3. In another
embodiment of a (III), o is 1; and Rx is CN.
In one embodiment of Formula (III), X is heteroaryl; n the heteroaryl
represented by X is ally substituted with one or two R4;
Rx,at each ence, is independently selected from the group consisting of R5,
5, CO(O)H, CN, F, Cl, Br and I;
L1 is selected from the group consisting of (CR6R7)q, (CR6R7)s-C(O)-(CR6R7)r,and
(CR6R7)s-S(O)2-(CR6R7)r; and
Y2 is selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl,
C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are optionally fused to one benzene ring; wherein Y2 is
optionally substituted with one, two, or three substituents independently selected from the
group consisting of R8, OR8, SO2R8, CO(O)R8, NHR8, N(R8)2, C(O)H, OH, CN, NO2, F, Cl,
Br and I; or
L1 is a bond; and
Y2 is selected from the group consisting of C3-7 cycloalkyl, phenyl, and C3-7
heterocyclyl; wherein the C3-7 cycloalkyl, phenyl, and C3-7 heterocyclyl ented by Y2 are
optionally fused to one benzene ring; wherein each Y2 and each ring fused to Y2 are
optionally substituted with one substituent independently selected from the group consisting
of R8 and C(O)NHR8;
Z1 is selected from the group consisting of
O O O
OH N
, and H Rk ;
R2,at each occurrence, is independently C1-6 alkyl;
R4, at each occurrence, is ndently selected from the group consisting of OR12
and halogen;
R5, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, and cycloalkyl;
R6A is independently selected from the group consisting of hydrogen and C1-6 alkyl;
R6 and R7, at each occurrence, are each independently selected from the group
consisting of hydrogen, R15, and 15;
R8, at each occurrence, is ndently selected from the group consisting of C1-6
alkyl, C2-6 alkynyl, aryl, heterocyclyl, and cycloalkyl; wherein the R8 C1-6 alkyl, and C2-6
l are optionally substituted with one, two, or three substituents independently selected
from the group consisting of R16, OR16, SO2R16, C(O)R16, N(R16)2, OH, F, Cl, Br and I;
wherein the R8 aryl and heterocyclyl are optionally substituted with one substituent
independently selected from the group consisting of C1-6 alkyl, F, Cl, Br and I;
Rk, at each occurrence, is ndently C1-6 alkyl;
R12 and R13, at each occurrence, are each independently C1-4 alkyl;
R15, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, and aryl; wherein the R15 C1-4 alkyl is optionally tuted with one substituent
independently selected from the group consisting C1-4 alkoxy, and heterocycloalkyl;
R16, at each occurrence, is ndently selected from the group ting of C1-4
alkyl, aryl, heterocycloalkyl, and heteroaryl;
q is 1, 2, or 3;
s is 0;
r is 0, or 1;
m is 0;
n is 0, or 1;
o is 0, 1, or 2; and
p is 0.
Still r embodiment ns to a compound having Formula (III) selected from
the group consisting of
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(pyridinylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(pyridinylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-
hydroxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(1-
phenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{4-[2-
(dimethylamino)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
3-(1-benzyl-1H-pyrazolyl){8-[(5,6-difluoro-1,3-benzothiazolyl)carbamoyl]-
3,4-dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(4-
fluorophenyl)ethyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
chlorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
3-(1-benzyl-1H-pyrazolyl){8-[(6-fluoro-1,3-benzothiazolyl)carbamoyl]-3,4-
dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid;
3-(1-benzyl-1H-pyrazolyl){8-[(6-methoxy-1,3-benzothiazolyl)carbamoyl]-
3,4-dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-3,5-dimethyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
methylbenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
methoxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-
chlorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(benzyloxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
hydroxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{3-[2-
(dimethylamino)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzylmethyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzylmethyl-1H-pyrazolyl)pyridinecarboxylic acid;
3-(1-benzyl-1H-pyrazolyl){8-[(7-chloro-1,3-benzothiazolyl)carbamoyl]-3,4-
dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[6-
lidinyl)pyridinyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
phenyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
enzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
chlorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(pyridinylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzylcyano-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(naphthalenylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-(3-
methyl-1,2,4-oxadiazolyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
benzyl(hydroxymethyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(benzyloxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-
methyl{[6-(pyrrolidinyl)pyridinyl]methyl}-1H-pyrazolyl)pyridinecarboxylic
acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][13-(ethoxycarbonyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(dimethylamino)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
carboxymethyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
hydroxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,3-
dihydro-1H-indenyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
phenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,4-
dihydro-2H-chromenyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[2-
(dimethylamino)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
fluorobenzyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
hexylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-{[3-
(dimethylamino)propyl]amino}nitrobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-
fluoronitrobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[2-
(morpholinyl)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[3-
(dimethylamino)propoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(pyridinylmethoxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[2-
(dimethylamino)ethoxy]benzyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[3-
(dimethylamino)propynyl]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,3-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,5-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,5-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,6-
robenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
nitrobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(biphenylylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,2-
dimethylpropyl)-1H-pyrazolyl]pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
cyclohexylethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(trifluoromethyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(biphenylylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclopentylmethyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
formylbenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzylphenyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-
methyl(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-
phenylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{3-
[(dimethylamino)methyl]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(methylsulfonyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)cyclopropyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,5-
di-tert-butylbenzyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(morpholinylsulfonyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(4,4-
difluorocyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
uoromethyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
nylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(morpholinyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(morpholinyl)phenylpropyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(tert-butoxycarbonyl)piperidinyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-
methyl{2-[2-(morpholinyl)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(dimethylamino)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-
methyl{2-[3-(morpholinyl)propoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic
acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-
methyl[(1-methylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[2-(4-
chlorophenyl)-4,4-dimethylcyclohexenyl]methyl}-1H-pyrazolyl)pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)ethyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
{[(1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptyl]methyl}methyl-1H-pyrazol
yl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
{[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptyl]methyl}methyl-1H-pyrazol
yl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methylpropyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(2-
methoxyethoxy)benzyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-
[(1R,2R,4R)-bicyclo[2.2.1]heptenylmethyl]methyl-1H-pyrazolyl}pyridine
ylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,3-
dimethylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
methoxyphenylpropyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-
methoxyphenylbutyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
methoxyoxophenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
cyclohexylphenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(3-
methoxypropyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[3-
hydroxy(hydroxymethyl)methylpropoxy]benzyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-
methyl[2-(tetrahydro-2H-pyranylmethoxy)benzyl]-1H-pyrazolyl}pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
ioxanylmethoxy)benzyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethoxy)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(piperidinylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(methoxymethyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3,3-
yl(morpholinyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)-3,3-dimethylcyclohexyl]methyl}methyl-1H-pyrazolyl)pyridine
ylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(3-
methoxypropyl)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
N-(1,3-benzothiazolyl){5-(1-{[1-(2-methoxyethyl)cycloheptyl]methyl}
methyl-1H-pyrazolyl)[(methylsulfonyl)carbamoyl]pyridinyl}-1,2,3,4-
tetrahydroisoquinolinecarboxamide;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
{[(1R,2R,3R,5S)(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]heptyl]methyl}-1H-
pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[1-
cyclohexyl(morpholinyl)propyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-
methyl(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-
methyl({1-[3-(morpholinyl)propoxy]cycloheptyl}methyl)-1H-pyrazolyl]pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-
methoxy-3,3-dimethylcyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic
acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-
methyl{[1-(morpholinyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic
acid;
N-(1,3-benzothiazolyl)(5-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]
methyl-1H-pyrazolyl}[(methylsulfonyl)carbamoyl]pyridinyl)-1,2,3,4-
tetrahydroisoquinolinecarboxamide;
6-[8-(1,3-benzothiazolylcarbamoyl)methyl-3,4-dihydroisoquinolin-2(1H)-yl]
{5-methyl[(1-methylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-
methoxycyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({1-[2-
(1,1-dioxidothiomorpholinyl)ethoxy]cyclohexyl}methyl)methyl-1H-pyrazol
yl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
hydroxyethoxy)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(2,3-dimethoxypropoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridine
ylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(1,4-dioxanylmethoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-
methyl({1-[2-(morpholinyl)oxoethoxy]cyclohexyl}methyl)-1H-pyrazol
yl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(2,3-dihydroxypropoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridine
ylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,3-
dimethyl[2-(methylsulfonyl)ethoxy]cyclohexyl}methyl)methyl-1H-pyrazol
idinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethoxy)-3,3-dimethylcyclohexyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(1-
cyclohexylmethoxypropyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,3-
dimethyl[2-(methylamino)ethoxy]cyclohexyl}methyl)methyl-1H-pyrazolyl]pyridine-
2-carboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-
methyl[(2,6,6-trimethyltetrahydro-2H-pyranyl)methyl]-1H-pyrazolyl}pyridine
carboxylic acid; and therapeutically acceptable salts, metabolites, prodrugs, salts of
metabolites, and salts of prodrugs thereof.
In another aspect, the present invention es compounds of Formula (IV)
(R1)m (R2)n
N N Z1
(Rx)o
HN O
(R3)p N
X N
L1 Y2
(IV)
and therapeutically acceptable salts, metabolites, prodrugs, salts of metabolites, and salts of
prodrugs thereof, wherein X, L1, Y2, Z1, R1, R2, R3, m, n, and p are as described herein for
Formula (I); Rx is as described herein for substituents on Y1, and o is 0 or 1.
One embodiment of this invention pertains to compounds or therapeutically
acceptable salts thereof, which are useful as inhibitors of anti-apoptotic Bcl-xL proteins, the
compounds having Formula (IV)
(R1)m (R2)n
N N Z1
(Rx)o
HN O
(R3)p N
X N
L1 Y2
Formula (IV),
X is heteroaryl; wherein the heteroaryl represented by X is optionally substituted with
one, two, three, or four R4;
Rx is independently selected fromthe group consisting of R5, OR5, SR5, S(O)R5,
SO2R5, C(O)R5, 5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2, NHC(O)R5,
NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5, NH2,
NHC(O)NHR5, N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5,
C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5, SO2NH2,
, SO2N(R5)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I;
L1 is selected from the group consisting of (CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-
C(O)-(CR6R7)r, )s-S-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-
(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, (CR6R7)s-NR6A-(CR6R7)r, )s-S(O)2NR6A-
)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r; and
Y2 is ed from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl,
C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are optionally fused to one or two rings selected from the group
consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 heterocycloalkene; wherein Y2 is optionally tuted with one,
two, three, four, or five substituents independently selected from the group consisting of R8,
OR8, SR8, , SO2R8, C(O)R8, CO(O)R8, OC(O)R8, OC(O)OR8, NH2, NHR8, N(R8)2,
NHC(O)R8, NR8C(O)R8, NHS(O)2R8, )2R8, NHC(O)OR8, NR8C(O)OR8,
NH2, NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2,
C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSO2R8, C(O)NR8SO2R8,
SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; or
L1 is a bond; and
Y2 is selected from the group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl,
and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl, , and C3-7
heterocyclyl represented by Y2 are optionally fused to one or two rings selected from the
group consisting of C3-8 lkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 heterocycloalkene; wherein each Y2 and each ring fused to Y2 are
optionally substituted with one, two, three, four, or five substituents independently ed
from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, OC(O)R8,
OC(O)OR8, NH2, NHR8, N(R8)2, NHC(O)R8, NR8C(O)R8, 2R8, NR8S(O)2R8,
NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8,
NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8,
C(O)NHSO2R8, C(O)NR8SO2R8, SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN,
N3, NO2, F, Cl, Br and I;
Z1 is ed from the group consisting of C(O)OR9, C(O)NR10R11, C(O)R11,
O)R11, NR10C(O)NR10R11, OC(O)NR10R11, NR10C(O)OR9, C(=NOR10)NR10R11,
NR10C(=NCN)NR10R11, NR10S(O)2NR10R11, S(O)2R9, S(O)2NR10R11, N(R10)S(O)2R11,
NR10C(=NR11)NR10R11, R10R11, C(=NR10)NR10R11, halogen, NO2, and CN; or
Z1 is selected from the group consisting of
N O O HN N
O HN N O N O
OH N
N N
OH N
H N
, , N , , H ,
H O O O OH O O O
OH Rk
N O N Rk S OH
, H Rk , , H , O ,
O O O O
OH OH O O
N N N OH N Rk
H , H , H , H ,
O Rk
O O
O O O
O S N
S N S Rk
N N Rk N
H H O
H , , and ;
R1, at each occurrence, is independently selected from the group consisting of halo,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
R2, at each occurrence, is independently selected from the group consisting of
deuterium, halo, C1-6 alkyl, C2-6 l, C2-6 alkynyl, and C1-6 haloalkyl;
two R2 that are attached to the same carbon atom, together with said carbon atom,
optionally form a ring selected from the group consisting of heterocycloalkyl,
heterocycloalkenyl, cycloalkyl, and cycloalkenyl;
R3, at each occurrence, is independently selected from the group consisting of halo,
C1-6 alkyl, C2-6 alkenyl, C2-6 l, and C1-6 haloalkyl;
R4, at each occurrence, is independently selected from the group ting of
NR12R13, OR12, CN, NO2, halogen, C(O)OR12, C(O)NR12R13, NR12C(O)R13, NR12S(O)2R14,
NR12S(O)R14, S(O)2R14, S(O)R14 and R14;
R5 is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, heterocyclyl, lkyl, and cycloalkenyl;
R6A is independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
R6 and R7, at each occurrence, are each independently selected from the group
consisting of hydrogen, R15, OR15, SR15, S(O)R15, SO2R15, C(O)R15, CO(O)R15, OC(O)R15,
OC(O)OR15, NH2, NHR15, N(R15)2, NHC(O)R15, NR15C(O)R15, NHS(O)2R15, NR15S(O)2R15,
NHC(O)OR15, NR15C(O)OR15, NH2, NHC(O)NHR15, NHC(O)N(R15)2,
O)NHR15, NR15C(O)N(R15)2, C(O)NH2, C(O)NHR15, C(O)N(R15)2, C(O)NHOH,
C(O)NHOR15, C(O)NHSO2R15, C(O)NR15SO2R15, , 15, SO2N(R15)2,
CO(O)H, C(O)H, OH,CN, N3, NO2, F, Cl, Br and I;
R8, at each occurrence, is independently selected from the group ting of C1-6
alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, aryl, heterocyclyl, cycloalkyl, and
lkenyl; wherein the R8 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl are
optionally substituted with one, two, three, four, five, or six substituents independently
selected from the group consisting of R16, OR16, SR16, S(O)R16, SO2R16, C(O)R16, CO(O)R16,
OC(O)R16, OC(O)OR16, NH2, NHR16, N(R16)2, NHC(O)R16, NR16C(O)R16, NHS(O)2R16,
NR16S(O)2R16, NHC(O)OR16, NR16C(O)OR16, NHC(O)NH2, NHC(O)NHR16,
NHC(O)N(R16)2, NR16C(O)NHR16, NR16C(O)N(R16)2, C(O)NH2, C(O)NHR16, C(O)N(R16)2,
C(O)NHOH, C(O)NHOR16, C(O)NHSO2R16, C(O)NR16SO2R16, SO2NH2, SO2NHR16,
16)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; wherein the R8 aryl,
heterocyclyl, lkyl, and cycloalkenyl are optionally substituted with one, two, or three
substituents independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C1-6 haloalkyl, NH2, C(O)NH2, , C(O)H, (O), OH, CN, NO2, OCF3,
OCF2CF3, F, Cl, Br and I;
R9 is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, lkyl, phenyl and (CH2)1-4 phenyl; and
R10 and R11, at each occurrence, are each independently selected from the group
consisting of hydrogen, C1-6 alkyl, C2-6 l, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 haloalkyl,
phenyl and (CH2)1phenyl; or
R10 and R11, or R10 and R9, together with the atom to which each is attached are
combined to form a heterocyclyl;
Rk, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C2-6 alkenyl, C2-6 l, C3-7 heterocycloalkyl, C3-7 lkyl and C1-6 haloalkyl;
wherein the Rk C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are ally substituted with aryl,
heterocyclyl, cycloalkyl, or cycloalkenyl;
R12 and R13, at each occurrence, are each independently selected from the group
consisting of hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 l, C1-4 haloalkyl and (CH2)1-4
phenyl;
R14, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, C2-4 alkenyl, C2-4 l and C1-4 haloalkyl;
R12 and R13, or R12 and R14, at each occurrence, together with the atom to which each
is attached, are ally combined to form a heterocyclyl;
R15, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, C2-4 l, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, aryl, heterocyclyl,
cycloalkyl, and cycloalkenyl; wherein the R15 C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4
haloalkyl, and C1-4 hydroxyalkyl are optionally substituted with one, two, or three substituents
independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4
haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl, NH2, C(O)NH2, SO2NH2, C(O)H, C(O)OH, (O),
OH, CN, NO2, OCF3, 3, F, Cl, Br and I;
R16, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, aryl, heterocycloalkyl,
heterocycloalkenyl, aryl, cycloalkyl, and cycloalkenyl; wherein the R16 C1-4 alkyl, C2-4
alkenyl, C2-4 alkynyl, C1-4 haloalkyl, and C1-4 hydroxyalkyl are optionally substituted with one
tuent independently selected from the group consisting of OCH3, OCH2CH2OCH3, and
OCH2CH2NHCH3;
q is 1, 2, or 3;
s is 0, 1, 2, or 3;
r is 0, 1, 2, or 3;
wherein the sum of s and r is 0, 1, or 2;
m is 0, 1, 2, or 3;
n is 0, 1, 2, 3, 4, 5, or 6;
o is 0 or 1; and
p is 0, 1, or 2.
In one embodiment of Formula (IV), m is 0, 1, 2, or 3; n is 0, 1, 2, 3, 4, 5, or 6; and p
is 0, 1, or 2. In another embodiment of Formula (IV), n is 0 or 1. In another embodiment of
Formula (IV), n is 0 or 1; and each R2 is independently deuterium or C1-6 alkyl. In another
ment of a (IV), m, n, and p are 0.
In one embodiment of Formula (IV), X is heteroaryl, which is optionally substituted
with one, two, three or four R4. In another embodiment of Formula (IV), X is heteroaryl,
which is unsubstituted. In another ment of Formula (IV), X is heteroaryl, which is
substituted with one R4. In another embodiment of Formula (IV), X is heteroaryl, which is
substituted with two R4. In another embodiment of Formula (IV), X is heteroaryl, which is
substituted with one R4, and R4 is OR12 or halogen. In another embodiment of Formula (IV),
X is heteroaryl, which is substituted with two R4, and each R4 is independently OR12 or
halogen. In another embodiment of Formula (IV), X is heteroaryl, which is substituted with
one R4, and R4 is Cl, F, or methoxy. In r ment of Formula (IV), X is heteroaryl,
which is tuted with two R4, and each R4 is independently F.
In one embodiment of Formula (IV), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl,
thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-
b]pyridinyl, imidazo[1,2-a]pyrazinyl, or o[1,2-b]pyridazinyl, which are optionally
substituted with one, two, three or four R4. In another embodiment of Formula (IV), X is
benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,
thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-
b]pyridazinyl, which are unsubstituted. In another ment of Formula (IV), X is
benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,
thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or o[1,2-
b]pyridazinyl, which are substituted with one R4. In another embodiment of Formula (IV), X
is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-
a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or
imidazo[1,2-b]pyridazinyl, which are tuted with two R4. In another embodiment of
Formula (IV), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,
imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-
a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are substituted with one R4, and R4 is OR12
or halogen. In r embodiment of Formula (IV), X is benzo[d]thiazolyl, thiazolo[5,4-
b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,
thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are
tuted with two R4, and each R4 is independently OR12 or halogen. In another
embodiment of Formula (IV), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-
dinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,
imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are substituted with one R4, and
R4 is Cl, F, or y. In another embodiment of Formula (IV), X is benzo[d]thiazolyl,
lo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-
c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl,
which are substituted with two R4, and each R4 is independently F.
In one embodiment of Formula (IV), X is benzo[d]thiazolyl, which is optionally
substituted with one, two, three or four R4. In another embodiment of Formula (IV), X is
benzo[d]thiazolyl, which is unsubstituted. In r embodiment of Formula (IV), X is
benzo[d]thiazolyl, which is substituted with one R4. In another embodiment of Formula (IV),
X is benzo[d]thiazolyl, which is substituted with two R4. In another embodiment of Formula
(IV), X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is OR12 or halogen. In
another embodiment of Formula (IV), X is benzo[d]thiazolyl, which is substituted with two
R4, and each R4 is independently OR12 or halogen. In another embodiment of Formula (IV),
X is d]thiazolyl, which is substituted with one R4, and R4 is Cl, F, or methoxy. In
another embodiment of a (IV), X is benzo[d]thiazolyl, which is substituted with two
R4, and each R4 is independently F.
In one ment of Formula (IV), Z1 is ed from the group consisting of
C(O)OR9, C(O)NR10R11, C(O)R11, NR10C(O)R11, NR10C(O)NR10R11, OC(O)NR10R11,
NR10C(O)OR9, C(=NOR10)NR10R11, NR10C(=NCN)NR10R11, O)2NR10R11, S(O)2R9,
S(O)2NR10R11, N(R10)S(O)2R11, NR10C(=NR11)NR10R11, C(=S)NR10R11, C(=NR10)NR10R11,
halogen, NO2, and CN; or Z1 is ed from the group consisting of
N O O
O HN N O N O HN N
OH N
N N
H N N
, , N , , H ,
H O O O O
O O OH O
N N S
OH Rk S OH
N O N Rk
, H Rk , , H , O ,
O O O O
OH OH O O
N N N OH N Rk
H , H , H , H ,
O Rk
O O
O O
O S N
S N S Rk
N N Rk N
H O
H , , and H .
In another embodiment of Formula (IV), Z1 is
O O Rk
HN N O O O
N S N
N S Rk
, N , H Rk N
, or H O .
In another
O O O
OH N
, or H Rk .
embodiment of Formula (IV), Z1 is In another
embodiment of Formula (IV), Z1 is .
In one embodiment of Formula (IV), L1 is selected from the group consisting of
(CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-C(O)-(CR6R7)r, (CR6R7)s-S-(CR6R7)r, (CR6R7)s-
S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, )s-
NR6A-(CR6R7)r, )s-S(O)2NR6A-(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r;and Y2 is
selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl, C4-7
cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 lkenyl,
phenyl, and C3-7 heterocyclyl are optionally fused to one or two rings selected from the group
consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 heterocycloalkene; n Y2 is optionally substituted with one,
two, three, four, or five tuents independently selected from the group consisting of R8,
OR8, SR8, S(O)R8, SO2R8, C(O)R8, 8, OC(O)R8, OC(O)OR8, NH2, NHR8, N(R8)2,
NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8, NHC(O)OR8, NR8C(O)OR8,
NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, 2,
C(O)NHR8, C(O)N(R8)2, OH, C(O)NHOR8, SO2R8, C(O)NR8SO2R8,
SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; or L1 is
a bond; and Y2 is selected from the group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7
heterocyclylrepresented by Y2 are optionally fused to one or two rings selected from the
group consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 heterocycloalkene; wherein each Y2 and each ring fused to Y2 are
optionally substituted with one, two, three, four, or five substituents ndently selected
from the group ting of R8, OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, OC(O)R8,
OC(O)OR8, NH2, NHR8, N(R8)2, R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8,
NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, )NHR8,
NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8,
C(O)NHSO2R8, C(O)NR8SO2R8, , SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN,
N3, NO2, F, Cl, Br and I.
In another embodiment of Formula (IV), L1 is selected from the group consisting of
(CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-C(O)-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-
NR6AC(O)-(CR6R7)r, (CR6R7)s-NR6A-(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r;and Y2 is
selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl, C4-7
cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are optionally fused to one or two benzene rings; wherein Y2 is
optionally substituted with one, two, or three substituents independently selected from the
group consisting of R8, OR8, SO2R8, CO(O)R8, NHR8, N(R8)2, C(O)H, OH, CN, NO2, F, Cl,
Br and I; or L1 is a bond; and Y2 is ed from the group consisting of C3-7 cycloalkyl,
phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, phenyl, and C3-7 heterocyclyl
represented by Y2 are optionally fused to one benzene ring; wherein each Y2 and each ring
fused to Y2 are optionally substituted with one substituent independently ed from the
group consisting of R8, C(O)NHR8, F, Cl, Br and I.
In another embodiment of Formula (IV), L1 is (CR6R7)q; and Y2 is selected from the
group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein
R6 and R7, at each occurrence, are R15 or hydrogen; and q is 1, 2, or 3.
In another embodiment of Formula (IV), L1 is selected from the group consisting of
(CR6R7)q, (CR6R7)s-C(O)-(CR6R7)r, and (CR6R7)s-S(O)2-(CR6R7)r; q is 1, 2, or 3; s is 0; r is 0
or 1; R6A is independently selected from the group ting of hydrogen, and C1-6 alkyl; and
R6 and R7, at each occurrence, are hydrogen.
In one embodiment of Formula (IV), o is 0. In another embodiment of Formula (IV),
o is 1. In another embodiment of Formula (IV), o is 0 or 1. In r embodiment of
Formula (IV), o is 1; and Rx is independently selected from the group ting of, R5, OR5,
SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, 5, OC(O)OR5, NH2, NHR5, N(R5)2,
NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5,
NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5,NR5C(O)N(R5)2, C(O)NH2,
C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, SO2R5, C(O)NR5SO2R5,
, SO2NHR5, SO2N(R5)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I. In
another embodiment of Formula (IV), o is 1; and Rx is independentlyselected fromthe group
consisting of R5, CO(O)R5, CO(O)H, CN, F, Cl, Br and I. In another ment of Formula
(IV), o is 1; Rx, at each occurrence, is independently selected from the group ting of R5,
CO(O)R5, CO(O)H, CN, F, Cl, Br and I; and R5 is independently selected from the group
consisting of C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, and cycloalkyl.
In another embodiment of Formula (IV), o is 1; Rx is independently selected from the group
consisting of R5, CN, F, Cl, Br and I; and R5, at each occurrence, is independently selected
from the group consisting of C1-2 alkyl, and C1 haloalkyl. In another embodiment of a
(IV), o is 1; Rx is R5 or CN; and R5 is CH3. In another embodiment of a (IV), o is 1;
and Rx is CN. In another embodiment of Formula (IV), o is 1; Rx is R5; and R5 is CH3..
In one ment of Formula (IV), X is heteroaryl; wherein the heteroaryl
represented by X is ally substituted with one or two R4;
Rx,at each occurrence, is independently selected from the group consisting of R5,
CO(O)R5, CO(O)H, CN, F, Cl, Br and I;
L1 is selected from the group ting of (CR6R7)q, (CR6R7)s-C(O)-(CR6R7)r,and
(CR6R7)s-S(O)2-(CR6R7); and
Y2 is selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl,
C4-7 lkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are ally fused to one benzene ring; n Y2 is
optionally substituted with one, two, or three substituents independently selected from the
group ting of R8, OR8, SO2R8, CO(O)R8, NHR8, N(R8)2, C(O)H, OH, CN, NO2, F, Cl,
Br and I; or
L1 is a bond; and
Y2 is selected from the group consisting of C3-7 cycloalkyl, phenyl, and C3-7
cyclyl; wherein the C3-7 lkyl, phenyl, and C3-7 heterocyclyl represented by Y2 are
optionally fused to one benzene ring; n each Y2 and each ring fused to Y2 are
optionally substituted with one substituent independently selected from the group consisting
of R8 and C(O)NHR8;
Z1 is selected from the group consisting of
O O O
OH N
, and H Rk ;
R2, at each occurrence, is independently C1-6 alkyl;
R4, at each occurrence, is independently selected from the group consisting of OR12
and halogen;
R5, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, and cycloalkyl;
R6A is independently selected from the group consisting of hydrogen and C1-6 alkyl;
R6 and R7, at each occurrence, are each independently selected from the group
consisting of hydrogen, R15, and CO(O)R15;
R8, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C2-6 alkynyl, aryl, heterocyclyl, and cycloalkyl; wherein the R8 C1-6 alkyl, and C2-6
alkynyl are optionally substituted with one, two, or three substituents independently ed
from the group consisting of R16, OR16, SO2R16, C(O)R16, 2, OH, F, Cl, Br and I;
wherein the R8 aryl and heterocyclyl are optionally substituted with one substituent
independently selected from the group consisting of C1-6 alkyl, F, Cl, Br and I;
Rk, at each occurrence, is ndently C1-6 alkyl;
R12 and R13, at each occurrence, are each independently C1-4 alkyl;
R15, at each ence, is independently selected from the group consisting of C1-4
alkyl, and aryl; wherein the R15 C1-4 alkyl is optionally substituted with one substituent
independently ed from the group consisting C1-4 alkoxy, and heterocycloalkyl;
R16, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, aryl, cycloalkyl, and heteroaryl;
q is 1, 2, or 3;
s is 0;
r is 0, or 1;
m is 0;
n is 0, or 1;
o is 0 or 1; and
p is 0.
Still another embodiment pertains to a compound having Formula (IV) selected from
the group consisting of
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
benzyl-1H-1,2,3-triazolyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
{[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptyl]methyl}methyl-1H-1,2,3-triazol
yl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-
methoxy-3,3-dimethylcyclohexyl)methyl]methyl-1H-1,2,3-triazolyl}pyridine
carboxylic acid; and therapeutically acceptable salts, metabolites, prodrugs, salts of
metabolites, and salts of prodrugs f.
In r aspect, the present invention provides compounds of a (V)
(R1)m (R2)n
N N Z1
(Rx)o
HN O
(R3)p
Y2
and therapeutically acceptable salts, metabolites, prodrugs, salts of metabolites, and salts of
prodrugs thereof, wherein X, L1, Y2, Z1, R1, R2, R3, m, n, and p are as described herein for
Formula (I); Rx is as described herein for substituents on Y1, and o is 0, 1, 2, 3, or 4.
One embodiment of this invention pertains to compounds or therapeutically
acceptable salts thereof, which are useful as inhibitors of anti-apoptotic Bcl-xL proteins, the
compounds having Formula (V)
(R1)m (R2)n
N N Z1
(Rx)o
HN O
(R3)p
Formula (V),
wherein
X is aryl; wherein the heteroaryl represented by X is optionally substituted with
one, two, three, or four R4;
Rx,at each occurrence, is independently selected from the group consisting of R5,
OR5, SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2,
NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5,
NHC(O)NH2, NHC(O)NHR5, N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2,
C(O)NHR5, R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5,
SO2NH2, SO2NHR5, SO2N(R5)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I;
L1 is selected from the group consisting of (CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-
C(O)-(CR6R7)r, (CR6R7)s-S-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-
(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, (CR6R7)s-NR6A-(CR6R7)r, )s-S(O)2NR6A-
(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r; and
Y2 is selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl,
C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl; n the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are optionally fused to one or two rings selected from the group
consisting of C3-8 lkane, C3-8 cycloalkene, e, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 cycloalkene; wherein Y2 is optionally substituted with one,
two, three, four, or five substituents independently selected from the group consisting of R8,
OR8, SR8, S(O)R8, SO2R8, , CO(O)R8, 8, OC(O)OR8, NH2, NHR8, ,
NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8, NHC(O)OR8, NR8C(O)OR8,
NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2,
C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSO2R8, C(O)NR8SO2R8,
SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; or
L1 is a bond; and
Y2 is selected from the group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl,
and C3-7 heterocyclyl; n the C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7
heterocyclyl represented by Y2 are optionally fused to one or two rings selected from the
group consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 heterocycloalkene; wherein each Y2 and each ring fused to Y2 are
ally substituted with one, two, three, four, or five substituents independently selected
from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, OC(O)R8,
OC(O)OR8, NH2, NHR8, , NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8,
NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8,
NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8,
C(O)NHSO2R8, C(O)NR8SO2R8, SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN,
N3, NO2, F, Cl, Br and I;
Z1 is selected from the group consisting of C(O)OR9, C(O)NR10R11, C(O)R11,
NR10C(O)R11, NR10C(O)NR10R11, OC(O)NR10R11, NR10C(O)OR9, C(=NOR10)NR10R11,
NR10C(=NCN)NR10R11, NR10S(O)2NR10R11, S(O)2R9, S(O)2NR10R11, N(R10)S(O)2R11,
NR10C(=NR11)NR10R11, C(=S)NR10R11, C(=NR10)NR10R11, halogen, NO2, and CN; or
Z1 is selected from the group consisting of
N O O HN N
O HN N O N O
OH N
N N
OH N
H N
, , N , , H ,
H O O O OH O O O
OH Rk N Rk S OH
N O
, H Rk , , H , O ,
O O O O
OH OH O O
N N N OH N Rk
H , H , H , H ,
O Rk
O O
O O
O S N
S N S Rk
N N Rk N
H H O
H , , and ;
R1, at each occurrence, is independently selected from the group consisting of halo,
C1-6 alkyl, C2-6 alkenyl, C2-6 l, and C1-6 kyl;
R2, at each ence, is independently selected from the group consisting of
ium, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 kyl;
two R2 that are attached to the same carbon atom, together with said carbon atom,
optionally form a ring selected from the group consisting of heterocycloalkyl,
heterocycloalkenyl, cycloalkyl, and cycloalkenyl;
R3, at each occurrence, is independently selected from the group consisting of halo,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
R4, at each occurrence, is independently selected from the group consisting of
NR12R13, OR12, CN, NO2, halogen, C(O)OR12, C(O)NR12R13, O)R13, NR12S(O)2R14,
NR12S(O)R14, S(O)2R14, S(O)R14 and R14;
R5, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, heterocyclyl,
cycloalkyl, and cycloalkenyl;
R6A is ndently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, and C1-6 kyl;
R6 and R7, at each occurrence, are each independently selected from the group
consisting of hydrogen, R15, OR15, SR15, S(O)R15, SO2R15, C(O)R15, CO(O)R15, OC(O)R15,
OC(O)OR15, NH2, NHR15, N(R15)2, NHC(O)R15, NR15C(O)R15, NHS(O)2R15, NR15S(O)2R15,
NHC(O)OR15, NR15C(O)OR15, NHC(O)NH2, NHR15, NHC(O)N(R15)2,
NR15C(O)NHR15, NR15C(O)N(R15)2, C(O)NH2, C(O)NHR15, C(O)N(R15)2, C(O)NHOH,
C(O)NHOR15, C(O)NHSO2R15, C(O)NR15SO2R15, SO2NH2, SO2NHR15, SO2N(R15)2,
CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I;
R8, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 kyl, aryl, heterocyclyl, cycloalkyl, and
cycloalkenyl; wherein the R8 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl are
ally substituted with one, two, three, four, five, or six substituents independently
selected from the group consisting of R16, OR16, SR16, S(O)R16, SO2R16, C(O)R16, CO(O)R16,
OC(O)R16, OC(O)OR16, NH2, NHR16, N(R16)2, NHC(O)R16, NR16C(O)R16, NHS(O)2R16,
O)2R16, NHC(O)OR16, O)OR16, NHC(O)NH2, NHC(O)NHR16,
NHC(O)N(R16)2, NR16C(O)NHR16, NR16C(O)N(R16)2, C(O)NH2, C(O)NHR16, C(O)N(R16)2,
C(O)NHOH, C(O)NHOR16, C(O)NHSO2R16, C(O)NR16SO2R16, SO2NH2, SO2NHR16,
SO2N(R16)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; wherein the R8 aryl,
heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substituted with one, two, or three
tuents independently selected from the group ting of C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C1-6 haloalkyl, NH2, 2, SO2NH2, C(O)H, (O), OH, CN, NO2, OCF3,
OCF2CF3, F, Cl, Br and I;
R9 is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, cycloalkyl, phenyl and (CH2)1-4 phenyl; and
R10 and R11, at each occurrence, are each ndently selected from the group
ting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 haloalkyl,
phenyl and (CH2)1phenyl; or
R10 and R11, or R10 and R9, together with the atom to which each is attached are
combined to form a heterocyclyl;
Rk, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 heterocycloalkyl, C3-7 lkyl and C1-6 haloalkyl;
wherein the Rk C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with aryl,
heterocyclyl, cycloalkyl, or cycloalkenyl;
R12 and R13, at each occurrence, are each independently selected from the group
consisting of hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl and (CH2)1-4
phenyl;
R14, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, C2-4 l, C2-4 alkynyl and C1-4 haloalkyl;
R12 and R13, or R12 and R14, at each occurrence, together with the atom to which each
is attached, are optionally combined to form a cyclyl;
R15, at each ence, is independently selected from the group consisting of C1-4
alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, aryl, heterocyclyl,
lkyl, and cycloalkenyl; wherein the R15 C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4
kyl, and C1-4 hydroxyalkyl are optionally tuted with one, two, or three substituents
independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4
haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl, NH2, C(O)NH2, SO2NH2, C(O)H, C(O)OH, (O),
OH, CN, NO2, OCF3, OCF2CF3, F, Cl, Br and I;
R16, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, aryl, heterocycloalkyl,
cycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R16 C1-4 alkyl, C2-4
alkenyl, C2-4 alkynyl, C1-4 haloalkyl, and C1-4 hydroxyalkyl are optionally substituted with one
substituent independently selected from the group ting of OCH3, OCH2CH2OCH3, and
OCH2CH2NHCH3;
q is 1, 2, or 3;
s is 0, 1, 2, or 3;
r is 0, 1, 2, or 3;
wherein the sum of s and r is 0, 1, or 2;
m is 0, 1, 2, or 3;
n is 0, 1, 2, 3, 4, 5, or 6;
o is 0, 1, 2, 3, or 4; and
p is 0, 1, or 2.
In one embodiment of Formula (V), m is 0, 1, 2, or 3; n is 0, 1, 2, 3, 4, 5, or 6; and p
is 0, 1, or 2. In another embodiment of Formula (V), n is 0 or 1. In another embodiment of
Formula (V), n is 0 or 1; and each R2 is independently deuterium or C1-6 alkyl. In another
ment of Formula (V), m, n, and p are 0.
In one embodiment of Formula (V), X is heteroaryl, which is optionally tuted
with one, two, three or four R4. In r embodiment of Formula (V), X is heteroaryl,
which is unsubstituted. In another embodiment of Formula (V), X is heteroaryl, which is
substituted with one R4. In another embodiment of Formula (V), X is heteroaryl, which is
substituted with two R4. In another embodiment of Formula (V), X is heteroaryl, which is
substituted with one R4, and R4 is OR12 or halogen. In another embodiment of Formula (V),
X is heteroaryl, which is substituted with two R4, and each R4 is independently OR12 or
halogen. In another embodiment of a (V), X is heteroaryl, which is substituted with
one R4, and R4 is Cl, F, or methoxy. In another embodiment of Formula (V), X is heteroaryl,
which is substituted with two R4, and each R4 is independently F.
In one embodiment of Formula (V), X is benzo[d]thiazolyl, lo[5,4-b]pyridinyl,
thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, lo[4,5-
b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are optionally
tuted with one, two, three or four R4. In another embodiment of Formula (V), X is
benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,
thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-
b]pyridazinyl, which are unsubstituted. In another embodiment of Formula (V), X is
d]thiazolyl, thiazolo[5,4-b]pyridinyl, lo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,
thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-
b]pyridazinyl, which are substituted with one R4. In another embodiment of Formula (V), X
is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-
a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, o[1,2-a]pyrazinyl, or
imidazo[1,2-b]pyridazinyl, which are substituted with two R4. In r embodiment of
Formula (V), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,
imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-
a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are substituted with one R4, and R4 is OR12
or halogen. In another embodiment of Formula (V), X is benzo[d]thiazolyl, thiazolo[5,4-
dinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,
thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are
substituted with two R4, and each R4 is independently OR12 or halogen. In another
ment of Formula (V), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-
c]pyridinyl, imidazo[1,2-a]pyridinyl, lo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,
imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are substituted with one R4, and
R4 is Cl, F, or methoxy. In another embodiment of Formula (V), X is benzo[d]thiazolyl,
thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, o[1,2-a]pyridinyl, thiazolo[5,4-
c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl,
which are substituted with two R4, and each R4 is independently F.
In one embodiment of Formula (V), X is benzo[d]thiazolyl, which is optionally
substituted with one, two, three or four R4. In another ment of Formula (V), X is
benzo[d]thiazolyl, which is tituted. In another embodiment of Formula (V), X is
benzo[d]thiazolyl, which is tuted with one R4. In another embodiment of Formula (V),
X is benzo[d]thiazolyl, which is substituted with two R4. In another embodiment of Formula
(V), X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is OR12 or halogen. In
another embodiment of Formula (V), X is d]thiazolyl, which is substituted with two R4,
and each R4 is independently OR12 or halogen. In another embodiment of Formula (V), X is
benzo[d]thiazolyl, which is substituted with one R4, and R4 is Cl, F, or methoxy. In another
ment of Formula (V), X is benzo[d]thiazolyl, which is substituted with two R4, and
each R4 is independently F.
In one embodiment of Formula (V), Z1 is selected from the group ting of
C(O)OR9, C(O)NR10R11, C(O)R11, NR10C(O)R11, NR10C(O)NR10R11, OC(O)NR10R11,
NR10C(O)OR9, C(=NOR10)NR10R11, NR10C(=NCN)NR10R11, NR10S(O)2NR10R11, S(O)2R9,
S(O)2NR10R11, N(R10)S(O)2R11, NR10C(=NR11)NR10R11, R10R11, C(=NR10)NR10R11,
halogen, NO2, and CN; or Z1 is selected from the group consisting of
N O O HN N
O HN N O N O
OH N
N N
OH N N
H , , N , , H ,
H O O O O OH O O O
N N S
OH Rk
N O N Rk S OH
, H Rk , , H , O ,
O O O O
OH OH O O
N N N OH N Rk
H , H , H , H ,
O Rk
O O O O
O S N
S N S Rk
N N Rk N
H O
H , , and H .
In another embodiment of Formula (V), Z1 is
O O Rk
O N O O
HN O
N S N
N S Rk
OH N H Rk N
, , , or H O .
In another
O O O
OH N
, or Rk .
embodiment of Formula (V), Z1 is H In another
embodiment of Formula (V), Z1 is .
In one embodiment of Formula (V), L1 is selected from the group consisting of
)q, )s-O-(CR6R7)r, (CR6R7)s-C(O)-(CR6R7)r, (CR6R7)s-S-(CR6R7)r, (CR6R7)s-
S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, (CR6R7)s-
NR6A-(CR6R7)r, (CR6R7)s-S(O)2NR6A-(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r;and Y2 is
selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl, C4-7
cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 lkenyl,
phenyl, and C3-7 cyclyl are optionally fused to oneor two rings selected from the group
consisting of C3-8 lkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 cycloalkene; wherein Y2 is optionally substituted with one,
two, three, four, or five substituents independently selected from the group consisting of R8,
OR8, SR8, S(O)R8, SO2R8, C(O)R8, 8, OC(O)R8, OC(O)OR8, NH2, NHR8, N(R8)2,
R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8, NHC(O)OR8, NR8C(O)OR8,
NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2,
C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSO2R8, C(O)NR8SO2R8,
SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; or L1 is
a bond; and Y2 is selected from the group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl,
, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7
heterocyclylrepresented by Y2 are optionally fused to one or two rings selected from the
group consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 heterocycloalkene; wherein each Y2 and each ring fused to Y2 are
optionally substituted with one, two, three, four, or five substituents independently selected
from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, 8,
OC(O)OR8, NH2, NHR8, N(R8)2, NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8,
NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHR8, NHC(O)N(R8)2, NR8C(O)NHR8,
NR8C(O)N(R8)2, C(O)NH2, R8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8,
C(O)NHSO2R8, C(O)NR8SO2R8, , SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN,
N3, NO2, F, Cl, Br and I.
In another embodiment of Formula (V), L1 is selected from the group consisting of
(CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-C(O)-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-
NR6AC(O)-(CR6R7)r, (CR6R7)s-NR6A-(CR6R7)r, and )s-NR6AS(O)2-(CR6R7)r;and Y2 is
selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl, C4-7
lkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are optionally fused to one or two benzene rings; wherein Y2 is
optionally substituted with one, two, or three tuents independently selected from the
group consisting of R8, OR8, SO2R8, CO(O)R8, NHR8, N(R8)2, C(O)H, OH, CN, NO2, F, Cl,
Br and I; or L1 is a bond; and Y2 is selected from the group consisting of C3-7 cycloalkyl,
phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, phenyl, and C3-7 heterocyclyl
ented by Y2 are optionally fused to one benzene ring; wherein each Y2 and each ring
fused to Y2 are optionally substituted with one substituent ndently ed from the
group consisting of R8, C(O)NHR8, F, Cl, Br and I.
In another embodiment of Formula (V), L1 is (CR6R7)q; and Y2 is selected from the
group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein
R6 and R7, at each occurrence, are R15 or hydrogen; and q is 1, 2, or 3.
In another embodiment of a (V), L1 is selected from the group consisting of
(CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-C(O)-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-
NR6AC(O)-(CR6R7)r, )s-NR6A-(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r; q is 1, 2,
or 3; s is 0; r is 0 or 1; R6A is independently ed from the group consisting of hydrogen,
and C1-6 alkyl; and R6 and R7, at each occurrence, are hydrogen.
In one embodiment of Formula (V), o is 0. In another embodiment of Formula (V), o
is 1. In another embodiment of Formula (V), o is 0 or 1. In another embodiment of Formula
(V), o is 0, 1, 2, 3, or 4. In another embodiment of Formula (V),o is 0, 1, 2, 3, or 4; and Rx, at
each occurrence, is independently selected from the group consisting of, R5, OR5, SR5,
S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2, NHC(O)R5,
NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2,
NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5,
C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5, SO2NH2,
5, SO2N(R5)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I. In another
ment of Formula (V), o is 1 or 2; and Rx, at each occurrence, is independently selected
from the group consisting of R5, CO(O)R5, CO(O)H, CN, F, Cl, Br and I. In another
ment of a (V), o is 1 or 2; Rx, at each occurrence, is independently selected
from the group consisting of R5, CO(O)R5, CO(O)H, CN, F, Cl, Br and I; and R5, at each
occurrence, is independently ed from the group consisting of C1-6 alkyl, C2-6 alkenyl, C1-
6 kyl, C1-6 hydroxyalkyl, aryl, and cycloalkyl. In another embodiment of Formula (V), o
is 1; Rx, at each occurrence, is ndently selected from the group consisting of R5, CN, F,
Cl, Br and I; and R5, at each occurrence, is independently selected from the group consisting
of C1-2 alkyl, and C1 haloalkyl. In another embodiment of a (V), o is 1 or 2; Rx is R5 or
CN; and R5 is CH3. In another embodiment of Formula (V), o is 1; and Rx is CN. In another
ment of Formula(V), o is 1; and Rx is CH3.
In one embodiment of Formula (V), X is heteroaryl; wherein the heteroaryl
represented by X is optionally substituted with one or two R4;
Rx,at each occurrence, is independently selected from the group consisting of R5,
CO(O)R5, CO(O)H, CN, F, Cl, Br and I;
L1 is selected from the group consisting of (CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-
C(O)-(CR6R7)r, )s-S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-(CR6R7)r, (CR6R7)s-NR6A-
(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r; and
Y2 is selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl,
C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl,
, and C3-7 heterocyclyl are optionally fused to one benzene ring; wherein Y2 is
ally substituted with one, two, or three substituents independently selected from the
group consisting of R8, OR8, SO2R8, CO(O)R8, NHR8, N(R8)2, C(O)H, OH, CN, NO2, F, Cl,
Br and I; or
L1 is a bond; and
Y2 is selected from the group consisting of C3-7 cycloalkyl, phenyl, and C3-7
heterocyclyl; wherein the C3-7 cycloalkyl, phenyl, and C3-7 heterocyclyl represented by Y2 are
optionally fused to one benzene ring; wherein each Y2 and each ring fused to Y2 are
optionally substituted with one substituent independently selected from the group ting
of R8 and C(O)NHR8;
Z1 is selected from the group consisting of
O O O
OH N
, and H Rk ;
R2, at each occurrence, is independently C1-6 alkyl;
R4, at each occurrence, is independently ed from the group consisting of OR12
and halogen;
R5, at each occurrence, is ndently selected from the group consisting of C1-6
alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, and cycloalkyl;
R6A is independently selected from the group consisting of hydrogen and C1-6 alkyl;
R6 and R7, at each occurrence, are each independently selected from the group
consisting of hydrogen, R15, and CO(O)R15;
R8, at each occurrence, is independently ed from the group consisting of C1-6
alkyl, C2-6 alkynyl, aryl, heterocyclyl, and lkyl; n the R8 C1-6 alkyl, and C2-6
alkynyl are optionally substituted with one, two, or three substituents independently selected
from the group consisting of R16, OR16, SO2R16, C(O)R16, N(R16)2, OH, F, Cl, Br and I;
wherein the R8 aryl and heterocyclyl are optionally tuted with one substituent
independently selected from the group ting of C1-6 alkyl, F, Cl, Br and I;
Rk, at each occurrence, is independently C1-6 alkyl;
R12 and R13, at each occurrence, are each independently C1-4 alkyl;
R15, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, and aryl; wherein the R15 C1-4 alkyl is optionally substituted with one substituent
ndently selected from the group consisting C1-4 alkoxy, and heterocycloalkyl;
R16, at each ence, is independently selected from the group consisting of C1-4
alkyl, aryl, heterocycloalkyl, and heteroaryl;
q is 1, 2, or 3;
s is 0;
r is 0, or 1;
m is 0;
n is 0, or 1;
o is 0, 1, 2, 3, or 4; and
p is 0.
Still another embodiment pertains to a nd having Formula (V) selected from
the group consisting of
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](4-
phenoxyphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](3-
yphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-(4-
nitrophenoxy)phenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-(4-
chlorophenoxy)phenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](3-
benzylphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexylmethyl)methylphenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](4-
methylphenoxyphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-
methylphenoxyphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-
methylphenoxyphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-
methylphenoxyphenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexylmethoxy)methylphenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][4-
(cyclohexyloxy)methylphenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexyloxy)methylphenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][4-
(cyclohexylmethoxy)methylphenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-cyano-
3-(cyclohexyloxy)phenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-chloro-
3-(cyclohexyloxy)phenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexylamino)methylphenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexyloxy)fluorophenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexyloxy)(trifluoromethyl)phenyl]pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-[(3,3-
dimethylcyclohexyl)oxy]methylphenyl}pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-
methyl[methyl(phenyl)amino]phenyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-[(3,3-
dimethylcyclohexyl)(methyl)amino]methylphenyl}pyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-
[(cyclohexylcarbonyl)(methyl)amino]methylphenyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-
methyl{methyl[(1-methylcyclohexyl)carbonyl]amino}phenyl)pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-cyano-
3-[(cyclohexylsulfonyl)(methyl)amino]phenyl}pyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-cyano-
tricyclo[3.3.1.13,7]decyl)pyrrolidinyl]phenyl}pyridinecarboxylic acid;and
therapeutically acceptable salts, metabolites, prodrugs, salts of lites, and salts of
prodrugs thereof.
In another aspect, the present invention provides compounds of Formula (VI)
(R1)m (R2)n
N N Z1
(Rx)o
HN O
(R3)p
X N
(VI)
and therapeutically acceptable salts, metabolites, prodrugs, salts of metabolites, and salts of
gs thereof, wherein X, L1, Y2, Z1, R1, R2, R3, m, n, and p are as described herein for
Formula (I); Rx is as bed herein for substituents on Y1, and o is 0, 1, 2, or 3.
One embodiment of this invention pertains to compounds or therapeutically
acceptable salts thereof, which are useful as inhibitors of anti-apoptotic Bcl-xL proteins, the
nds having Formula (VI)
(R1)m (R2)n
N N Z1
(Rx)o
HN O
(R3)p
X N
Formula (VI),
wherein
X is heteroaryl; wherein the heteroaryl represented by X is optionally substituted with
one, two, three, or four R4;
Rx,at each occurrence, is independently selected from the group consisting of R5,
OR5, SR5, S(O)R5, SO2R5, , CO(O)R5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2,
NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5,
NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2,
C(O)NHR5, C(O)N(R5)2, C(O)NHOH, OR5, C(O)NHSO2R5, C(O)NR5SO2R5,
SO2NH2, SO2NHR5, SO2N(R5)2, , C(O)H, OH, CN, N3, NO2, F, Cl, Br and I;
L1 is selected from the group consisting of (CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-
CR6R7)r, (CR6R7)s-S-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-
(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, (CR6R7)s-NR6A-(CR6R7)r, (CR6R7)s-S(O)2NR6A-
(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r; and
Y2 is selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl,
C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are ally fused to one or two rings selected from the group
consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 arene, C3-8
heterocycloalkane, and C3-8 heterocycloalkene; wherein Y2 is optionally substituted with one,
two, three, four, or five substituents independently selected from the group consisting of R8,
OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, OC(O)R8, R8, NH2, NHR8, N(R8)2,
NHC(O)R8, NR8C(O)R8, NHS(O)2R8, )2R8, NHC(O)OR8, )OR8,
NHC(O)NH2, NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2,
C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSO2R8, C(O)NR8SO2R8,
SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; or
L1 is a bond; and
Y2 is selected from the group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl,
and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7
heterocyclyl represented by Y2 are ally fused to one or two rings selected from the
group consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
cycloalkane, and C3-8 heterocycloalkene; wherein each Y2 and each ring fused to Y2 are
optionally substituted with one, two, three, four, or five substituents independently selected
from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, OC(O)R8,
OC(O)OR8, NH2, NHR8, N(R8)2, NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8,
NHC(O)OR8, NR8C(O)OR8, NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8,
NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, OH, C(O)NHOR8,
C(O)NHSO2R8, C(O)NR8SO2R8, SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN,
N3, NO2, F, Cl, Br and I;
Z1 is selected from the group consisting of C(O)OR9, C(O)NR10R11, C(O)R11,
NR10C(O)R11, NR10C(O)NR10R11, R10R11, NR10C(O)OR9, C(=NOR10)NR10R11,
NR10C(=NCN)NR10R11, NR10S(O)2NR10R11, S(O)2R9, S(O)2NR10R11, N(R10)S(O)2R11,
=NR11)NR10R11, C(=S)NR10R11, C(=NR10)NR10R11, halogen, NO2, and CN; or
Z1 is selected from the group consisting of
N O O N
O HN N O N O HN
OH N
N N
H N N
, , N , , H ,
H O O O O
N O O OH O
N S
OH Rk S OH
N O N Rk
, H Rk , , H , O ,
O O O O
OH OH O O
N N N OH N Rk
H , H , H , H ,
O Rk
O O
O O O
O S N
S N S Rk
N N Rk N
H O
H , , and H ;
R1, at each occurrence, is independently ed from the group consisting of halo,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
R2, at each occurrence, is independently selected from the group consisting of
deuterium, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
two R2 that are attached to the same carbon atom, together with said carbon atom,
optionally form a ring ed from the group consisting of cycloalkyl,
heterocycloalkenyl, cycloalkyl, and cycloalkenyl;
R3, at each occurrence, is independently selected from the group consisting of halo,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
R4, at each ence, is independently selected from the group consisting of
NR12R13, OR12, CN, NO2,halogen, C(O)OR12, C(O)NR12R13, NR12C(O)R13, NR12S(O)2R14,
NR12S(O)R14, S(O)2R14, S(O)R14 and R14;
R5, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C2-6 alkenyl, C2-6 l, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, cyclyl,
cycloalkyl, and cycloalkenyl;
R6A is independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, and C1-6 kyl;
R6 and R7, at each occurrence, are each independently selected from the group
consisting of hydrogen, R15, OR15, SR15, S(O)R15, SO2R15, 5, CO(O)R15, OC(O)R15,
OC(O)OR15, NH2, NHR15, N(R15)2, NHC(O)R15, NR15C(O)R15, NHS(O)2R15, NR15S(O)2R15,
NHC(O)OR15, NR15C(O)OR15, NH2, NHC(O)NHR15, NHC(O)N(R15)2,
NR15C(O)NHR15, NR15C(O)N(R15)2, C(O)NH2, C(O)NHR15, C(O)N(R15)2, C(O)NHOH,
C(O)NHOR15, C(O)NHSO2R15, C(O)NR15SO2R15, SO2NH2, SO2NHR15, SO2N(R15)2,
CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I;
R8, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C2-6 l, C2-6 alkynyl, C1-6 haloalkyl, aryl, heterocyclyl, cycloalkyl, and
cycloalkenyl; wherein the R8 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl are
optionally substituted with one, two, three, four, five, or six tuents independently
selected from the group consisting of R16, OR16, SR16, S(O)R16, SO2R16, C(O)R16, CO(O)R16,
OC(O)R16, OC(O)OR16, NH2, NHR16, N(R16)2, NHC(O)R16, NR16C(O)R16, NHS(O)2R16,
NR16S(O)2R16, NHC(O)OR16, NR16C(O)OR16, NHC(O)NH2, NHC(O)NHR16,
NHC(O)N(R16)2, NR16C(O)NHR16, NR16C(O)N(R16)2, C(O)NH2, C(O)NHR16, C(O)N(R16)2,
C(O)NHOH, C(O)NHOR16, C(O)NHSO2R16, 16SO2R16, SO2NH2, SO2NHR16,
SO2N(R16)2, , C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; wherein the R8 aryl,
heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substituted with one, two, or three
substituents independently selected from the group consisting of C1-6 alkyl, C2-6 l, C2-6
alkynyl, C1-6 haloalkyl, NH2, C(O)NH2, SO2NH2, C(O)H, (O), OH, CN, NO2, OCF3,
OCF2CF3, F, Cl, Br and I;
R9 is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
kyl, cycloalkyl, phenyl and (CH2)1-4 phenyl; and
R10 and R11, at each occurrence, are each independently selected from the group
consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 l, C3-6 cycloalkyl, C1-6 kyl,
phenyl and (CH2)1phenyl; or
R10 and R11, or R10 and R9, together with the atom to which each is attached are
combined to form a heterocyclyl;
Rk, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 heterocycloalkyl, C3-7 cycloalkyl and C1-6 haloalkyl;
wherein the Rk C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with aryl,
heterocyclyl, lkyl, or cycloalkenyl;
R12 and R13, at each ence, are each independently selected from the group
consisting of hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl and (CH2)1-4
phenyl;
R14, at each occurrence, is independently ed from the group consisting of C1-4
alkyl, C2-4 alkenyl, C2-4 alkynyl and C1-4 haloalkyl;
R12 and R13, or R12 and R14, at each occurrence, together with the atom to which each
is attached, are optionally combined to form a heterocyclyl;
R15, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, aryl, heterocyclyl,
cycloalkyl, and cycloalkenyl; wherein the R15 C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4
haloalkyl, and C1-4 hydroxyalkyl are ally substituted with one, two, or three substituents
independently selected from the group ting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4
haloalkyl, C1-4 hydroxyalkyl, C1-4 , aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl, NH2, C(O)NH2, SO2NH2, C(O)H, C(O)OH, (O),
OH, CN, NO2, OCF3, OCF2CF3, F, Cl, Br and I;
R16, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, C2-4 l, C2-4 alkynyl, C1-4 haloalkyl, C1-4 yalkyl, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, lkyl, and cycloalkenyl; wherein the R16 C1-4 alkyl, C2-4
alkenyl, C2-4 alkynyl, C1-4 haloalkyl, and C1-4 hydroxyalkyl are optionally substituted with one
substituent independently ed from the group consisting of OCH3, OCH2CH2OCH3, and
2NHCH3;
q is 1, 2, or 3;
s is 0, 1, 2, or 3;
r is 0, 1, 2, or 3;
wherein the sum of s and r is 0, 1, or 2;
m is 0, 1, 2, or 3;
n is 0, 1, 2, 3, 4, 5, or 6;
o is 0, 1, 2, or 3; and
p is 0, 1, or 2.
In one embodiment of Formula (VI), m is 0, 1, 2, or 3; n is 0, 1, 2, 3, 4, 5, or 6; and p
is 0, 1, or 2. In another embodiment of Formula (VI), n is 0 or 1. In another embodiment of
Formula (VI), n is 0 or 1; and each R2 is independently deuterium or C1-6 alkyl. In another
embodiment of Formula (VI), m, n, and p are 0.
In one embodiment of Formula (VI), X is heteroaryl, which is optionally substituted
with one, two, three or four R4. In another embodiment of a (VI), X is aryl,
which is unsubstituted. In another embodiment of Formula (VI), X is heteroaryl, which is
tuted with one R4. In another embodiment of Formula (VI), X is heteroaryl, which is
substituted with two R4. In another embodiment of Formula (VI), X is heteroaryl, which is
substituted with one R4, and R4 is OR12 or halogen. In another ment of Formula (VI),
X is heteroaryl, which is substituted with two R4, and each R4 is independently OR12 or
halogen. In another embodiment of Formula (VI), X is heteroaryl, which is substituted with
one R4, and R4 is Cl, F, or methoxy. In another embodiment of Formula (VI), X is heteroaryl,
which is substituted with two R4, and each R4 is independently F.
In one embodiment of Formula (VI), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl,
lo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-
b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are optionally
tuted with one, two, three or four R4. In another embodiment of Formula (VI), X is
benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,
thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-
b]pyridazinyl, which are unsubstituted. In r embodiment of Formula (VI), X is
benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,
thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-
b]pyridazinyl, which are substituted with one R4. In r embodiment of Formula (VI), X
is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-
a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or
imidazo[1,2-b]pyridazinyl, which are substituted with two R4. In another embodiment of
Formula (VI), X is benzo[d]thiazolyl, lo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,
imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl, imidazo[1,2-
a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are substituted with one R4, and R4 is OR12
or halogen. In r embodiment of Formula (VI), X is d]thiazolyl, thiazolo[5,4-
b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,
thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which are
substituted with two R4, and each R4 is independently OR12 or halogen. In another
embodiment of Formula (VI), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-
c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,
imidazo[1,2-a]pyrazinyl, or o[1,2-b]pyridazinyl, which are substituted with one R4, and
R4 is Cl, F, or methoxy. In another ment of Formula (VI), X is benzo[d]thiazolyl,
thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolo[5,4-
c]pyridinyl, lo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl,
which are tuted with two R4, and each R4 is independently F.
In one embodiment of Formula (VI), X is benzo[d]thiazolyl, which is optionally
substituted with one, two, three or four R4. In another embodiment of Formula (VI), X is
benzo[d]thiazolyl, which is unsubstituted. In another embodiment of Formula (VI), X is
benzo[d]thiazolyl, which is substituted with one R4. In another embodiment of Formula (VI),
X is benzo[d]thiazolyl, which is substituted with two R4. In r embodiment of Formula
(VI), X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is OR12 or n. In
another embodiment of Formula (VI), X is benzo[d]thiazolyl, which is substituted with two
R4, and each R4 is independently OR12 or halogen. In another embodiment of Formula (VI),
X is benzo[d]thiazolyl, which is substituted with one R4, and R4 is Cl, F, or methoxy. In
another embodiment of Formula (VI), X is benzo[d]thiazolyl, which is substituted with two
R4, and each R4 is independently F.
In one ment of Formula (VI), Z1 is selected from the group consisting of
C(O)OR9, 10R11, C(O)R11, NR10C(O)R11, NR10C(O)NR10R11, OC(O)NR10R11,
NR10C(O)OR9, 10)NR10R11, NR10C(=NCN)NR10R11, NR10S(O)2NR10R11, S(O)2R9,
S(O)2NR10R11, N(R10)S(O)2R11, =NR11)NR10R11, C(=S)NR10R11, C(=NR10)NR10R11,
halogen, NO2, and CN; or Z1 is selected from the group consisting of
N O O N
O HN N O N O HN
N OH N
N OH N
H , N N
, , , H ,
H O O O OH O O O
OH Rk N Rk S OH
N O
, H Rk , , H , O ,
O O O O
OH OH O O
N N N OH N Rk
H , H , H , H ,
O Rk
O O
O O O
O S N
S N S Rk
N N Rk N
H O
H , , and H .
In another embodiment of a (VI), Z1 is
O O Rk
HN N O O
N S
N S Rk
OH N H Rk N
, , , or H O .
In another
O O O
OH N
, or .
embodiment of Formula (VI), Z1 is H Rk
In another
OH
embodiment of Formula (VI), Z1 is .
In one embodiment of Formula (VI), L1 is selected from the group consisting of
(CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-C(O)-(CR6R7)r, (CR6R7)s-S-(CR6R7)r, (CR6R7)s-
S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, (CR6R7)s-
NR6A-(CR6R7)r, (CR6R7)s-S(O)2NR6A-(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r;and Y2 is
ed from the group consisting of C3-11 ed chain alkyl, C3-7 lkyl, C4-7
cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are optionally fused to one or two rings selected from the group
consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
heterocycloalkane, and C3-8 heterocycloalkene; wherein Y2 is ally substituted with one,
two, three, four, or five substituents independently ed from the group consisting of R8,
OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, OC(O)R8, OC(O)OR8, NH2, NHR8, N(R8)2,
NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8, NHC(O)OR8, NR8C(O)OR8,
NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2,
C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, SO2R8, C(O)NR8SO2R8,
SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; or L1 is
a bond; and Y2 is selected from the group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl,
, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7
heterocyclyl represented by Y2 are optionally fused to one or two rings selected from the
group consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8
cycloalkane, and C3-8 heterocycloalkene; wherein each Y2 and each ring fused to Y2 are
optionally substituted with one, two, three, four, or five substituents independently selected
from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, OC(O)R8,
OC(O)OR8, NH2, NHR8, N(R8)2, NHC(O)R8, NR8C(O)R8, NHS(O)2R8, )2R8,
NHC(O)OR8, )OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8,
NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, OH, C(O)NHOR8,
C(O)NHSO2R8, C(O)NR8SO2R8, SO2NH2, SO2NHR8, SO2N(R8)2, , C(O)H, OH, CN,
N3, NO2, F, Cl, Br and I.
In another ment of Formula (VI), L1 is ed from the group consisting of
(CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-C(O)-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-
NR6AC(O)-(CR6R7)r, (CR6R7)s-NR6A-(CR6R7)r,and (CR6R7)s-NR6AS(O)2-(CR6R7)r;and Y2 is
selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl, C4-7
cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 lkenyl,
phenyl, and C3-7 heterocyclyl are optionally fused to one or two benzene rings; wherein Y2 is
optionally substituted with one, two, or three substituents independently selected from the
group ting of R8, OR8, SO2R8, CO(O)R8, NHR8, N(R8)2, C(O)H, OH, CN, NO2, F, Cl,
Br and I; or L1 is a bond; and Y2 is selected from the group consisting of C3-7 cycloalkyl,
phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, phenyl, and C3-7 heterocyclyl
represented by Y2 are optionally fused to one benzene ring; wherein each Y2 and each ring
fused to Y2 are optionally substituted with one substituent independently ed from the
group consisting of R8, C(O)NHR8, F, Cl, Br and I.
In another embodiment of a (VI), L1 is (CR6R7)q; and Y2 is selected from the
group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein
R6 and R7, at each occurrence, are R15 or hydrogen; and q is 1, 2, or 3.
In another embodiment of a (VI), L1 is selected from the group consisting of
)q, (CR6R7)s-O-(CR6R7)r,(CR6R7)s-C(O)-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-
NR6AC(O)-(CR6R7)r, (CR6R7)s-NR6A-(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r; q is 1, 2,
or 3; s is 0; r is 0 or 1; R6A is independently selected from the group consisting of en,
and C1-6 alkyl;and R6 and R7, at each occurrence, are hydrogen.
In one embodiment of Formula (VI), o is 0. In another embodiment of Formula (VI),
o is 1. In another ment of Formula (VI), o is 0 or 1. In another embodiment of
Formula (VI), o is 0, 1, 2, or 3. In another embodiment of Formula (VI),o is 0, 1, 2, or 3; and
Rx, at each occurrence, is independently selected from the group consisting of, R5, OR5, SR5,
S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2, NHC(O)R5,
NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2,
NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5,
C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5, SO2NH2,
SO2NHR5, SO2N(R5)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I. In r
embodiment of Formula (VI), o is 1 or 2; and Rx, at each occurrence, is independently
selected from the group consisting of R5, CO(O)R5, CO(O)H, CN, F, Cl, Br and I. In another
embodiment of Formula (VI), o is 1 or 2; Rx, at each occurrence,is independently ed
from the group consisting of R5, CO(O)R5, CO(O)H, CN, F, Cl, Br and I; and R5, at each
occurrence, is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C1-
6 haloalkyl, C1-6 hydroxyalkyl, aryl, and cycloalkyl. In another embodiment of Formula (VI),
o is 1; Rx, at each occurrence, is independently selected from the group consisting of R5, CN,
F, Cl, Br and I; and R5, at each occurrence, is ndently selected from the group
consisting of C1-2 alkyl, and C1 haloalkyl. In another embodiment of a (VI), o is 1 or
2; Rx is R5 or CN; and R5 is CH3. In another embodiment of Formula (VI), o is 1; and Rx is
CN. In another embodiment of Formula (VI), o is 1; and Rx is CH3.
In one embodiment of a(VI), X is heteroaryl; wherein the heteroaryl
represented by X is optionally substituted with one or two R4;
Rx,at each occurrence, is independently selected from the group consisting of R5,
CO(O)R5, CO(O)H, CN, F, Cl, Br and I;
L1 is selected from the group consisting of (CR6R7)q, )s-O-(CR6R7)r, (CR6R7)s-
C(O)-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, )s-NR6AC(O)-(CR6R7)r, (CR6R7)s-NR6A-
)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r; and
Y2 is ed from the group ting of C3-11 branched chain alkyl, C3-7 lkyl,
C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl,
phenyl, and C3-7 heterocyclyl are optionally fused to one benzene ring; wherein Y2 is
optionally substituted with one, two, or three tuents independently selected from the
group consisting of R8, OR8, SO2R8, CO(O)R8, NHR8, N(R8)2, C(O)H, OH, CN, NO2, F, Cl,
Br and I; or
L1 is a bond; and
Y2 is selected from the group consisting of C3-7 cycloalkyl, phenyl, and C3-7
heterocyclyl; wherein the C3-7 cycloalkyl, phenyl, and C3-7 heterocyclyl represented by Y2 are
optionally fused to one benzene ring; wherein each Y2 and each ring fused to Y2 are
optionally tuted with one substituent independently selected from the group consisting
of R8 and C(O)NHR8;
Z1 is selected from the group consisting of
O O O
OH N
, and Rk ;
H
R2, at each occurrence, is independently C1-6 alkyl;
R4, at each ence, is independently ed from the group consisting of OR12
and halogen;
R5, at each occurrence, is independently selected from the group consisting of C1-6
alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, and cycloalkyl;
R6A is independently selected from the group consisting of hydrogen and C1-6 alkyl;
R6 and R7, at each occurrence, are each independently selected from the group
consisting of hydrogen, R15, and CO(O)R15;
R8, at each occurrence, is ndently selected from the group consisting of C1-6
alkyl, C2-6 alkynyl, aryl, heterocyclyl, and cycloalkyl; n the R8 C1-6 alkyl, and C2-6
alkynyl are optionally substituted with one, two, or three substituents independently selected
from the group consisting of R16, OR16, , C(O)R16, N(R16)2, OH, F, Cl, Br and I;
wherein the R8 aryl and heterocyclyl are optionally substituted with one substituent
independently selected from the group consisting of C1-6 alkyl, F, Cl, Br and I;
Rk, at each occurrence, is independently C1-6 alkyl;
R12 and R13, at each occurrence, are each independently C1-4 alkyl;
R15, at each ence, is independently selected from the group ting of C1-4
alkyl, and aryl; wherein the R15 C1-4 alkyl is optionally substituted with one substituent
independently selected from the group consisting C1-4 alkoxy, and heterocycloalkyl;
R16, at each occurrence, is independently selected from the group consisting of C1-4
alkyl, aryl, heterocycloalkyl, and heteroaryl;
q is 1, 2, or 3;
s is 0;
r is 0, or 1;
m is 0;
n is 0, or 1;
o is 0, 1, 2, 3, or 4; and
p is 0.
Still another ment pertains to a compound having Formula (VI) selected from
the group consisting of
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-
(cyclohexyloxy)-3'-methyl-3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-
(cyclohexyloxy)-3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-phenoxy-
3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-
2'-phenoxy-3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-
2'-[methyl(phenyl)amino]-3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-
[cyclohexyl(methyl)amino]-3'-methyl-3,4'-bipyridinecarboxylic acid;
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-cyano-2'-
[cyclohexyl(methyl)amino]-3,4'-bipyridinecarboxylic acid;
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-
2'-(piperidinyl)-3,4'-bipyridinecarboxylic acid; and therapeutically acceptable salts,
metabolites, gs, salts of metabolites, and salts of prodrugs thereof.
Pharmaceutical Compositions, Combination Therapies, Methods of Treatment, and
Administration
Another embodiment comprises pharmaceutical compositions comprising a
compound having Formula (I) and an excipient.
Still another embodiment comprises methods of treating cancer in a mammal
comprising administering thereto a therapeutically acceptable amount of a compound having
Formula (I).
Still another embodiment comprises methods of treating autoimmune disease in a
mammal comprising administering thereto a therapeutically able amount of a
compound having Formula (I).
Still another ment pertains to compositions for treating es during which
anti-apoptotic Bcl-xL proteins are expressed, said compositions comprising an excipient and a
therapeutically effective amount of the compound having a (I).
Still another embodiment pertains to s of treating disease in a patient during
which anti-apoptotic Bcl-xLproteins are expressed, said methods comprising administering to
the t a therapeutically ive amount of a compound having Formula (I).
Still r embodiment pertains to compositions for treating bladder cancer, brain
cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia,
colorectal , esophageal cancer, hepatocellular cancer, lymphoblastic leukemia,
follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,
enous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer,
prostate cancer, small cell lung cancer or spleen cancer, said compositions comprising an
excipient and a therapeutically effective amount of the compound having Formula (I).
Still another embodiment pertains to methods of treating bladder cancer, brain cancer,
breast cancer, bone marrow cancer, al cancer, chronic lymphocytic leukemia, colorectal
cancer, esophageal cancer, hepatocellular cancer, lymphoblastic ia, follicular
lymphoma, lymphoid malignancies of T-cell or B-cell , melanoma, myelogenous
leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer,
small cell lung cancer or spleen cancer in a patient, said methods comprising administering to
the patient a therapeutically effective amount of a compound having Formula (I).
Still another embodiment ns to compositions for treating diseases during which
are expressed anti-apoptotic Bcl-xL proteins, said compositions comprising an excipient and a
eutically effective amount of the compound having Formula (I) and a eutically
effective amount of one additional therapeutic agent or more than one additional therapeutic
agent.
Still another embodiment pertains to methods of treating disease in a patient during
which are expressed anti-apoptotic Bcl-xL proteins, said methods comprising administering to
the patient a therapeutically effective amount of a compound having Formula (I) and a
therapeutically effective amount of one additional therapeutic agent or more than one
onal therapeutic agent.
Still another embodiment pertains to compositions for treating bladder cancer, brain
cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia,
ctal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic ia,
follicular lymphoma, lymphoid ancies of T-cell or B-cell origin, melanoma,
myelogenous leukemia, a, oral cancer, ovarian cancer, non-small cell lung cancer,
chronic lymphocytic leukemia, a, prostate cancer, small cell lung cancer or spleen
cancer, said compositions comprising an ent and a therapeutically effective amount of
the nd having Formula (I) and a therapeutically effective amount of one additional
therapeutic agent or more than one additional therapeutic agent.
Still another ment pertains to methods of treating bladder , brain cancer,
breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal
cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular
ma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous
leukemia, myeloma, oral cancer, ovarian , non-small cell lung cancer, chronic
lymphocytic leukemia, myeloma, prostate , small cell lung cancer or spleen cancer in a
patient, said methods comprising administering to the patient a therapeutically effective
amount of the compound having Formula (I) and a therapeutically effective amount of one
additional therapeutic agent or more than one additional therapeutic agent.
Metabolites of compounds having Formula (I), produced by in vitro or in vivo
metabolic processes, may also have utility for treating es associated with poptotic
Bcl-xL proteins.
Certain precursor compounds which may be lized in vitro or in vivo to form
nds having Formula (I) may also have utility for treating diseases associated with
expression of anti-apoptotic Bcl-xL ns.
Compounds having Formula (I) may exist as acid addition salts, basic addition salts
or zwitterions. Salts of the compounds are prepared during isolation or following
purification of the compounds. Acid addition salts of the compounds are those derived from
the reaction of the compounds with an acid. For example, the acetate, e, alginate,
bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, rate,
camphorsufonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate,
heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate,
maleate, mesitylenesulfonate, esulfonate, naphthylenesulfonate, nicotinate, oxalate,
pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, te,
thiocyanate, trichloroacetic, trifluoroacetic, para-toluenesulfonate, and undecanoate salts of
the compounds are contemplated as being embraced by this invention. Basic addition salts
of the nds are those derived from the reaction of the compounds with the hydroxide,
carbonate or bicarbonate of cations such as lithium, , potassium, calcium, and
magnesium.
The compounds having Formula (I) may be administered, for example, bucally,
ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperitoneally
intrasternally, enously, subcutaneously), rectally, topically, transdermally or vaginally.
Therapeutically effective amounts of compounds having Formula (I) depend on the
ent of the treatment, the disorder being treated and the severity thereof, the ition
containing the compound, the time of administration, the route of stration, the duration
of treatment, the compound potency, its rate of clearance and whether or not another drug is
inistered. The amount of a compound of this invention having Formula (I) used to
make a composition to be administered daily to a patient in a single dose or in d doses
is from about 0.03 to about 200 mg/kg body weight. Single dose compositions contain these
amounts or a ation of submultiples thereof.
Compounds having Formula (I) may be administered with or without an excipient.
ents include, for example, encapsulating materials or additives such as absorption
accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents,
disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants,
perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners,
solubilizers, wetting agents and mixtures thereof.
Excipients for preparation of compositions comprising a compound having Formula
(I) to be stered orally in solid dosage form include, for example, agar, alginic acid,
aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor
oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil,
povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid
esters, gelatin, germ oil, e, glycerol, groundnut oil, hydroxypropylmethyl cellulose,
isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt,
mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch,
povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium
carboxymethyl ose, sodium phosphate salts, sodium lauryl sulfate, sodium ol,
soybean oil, stearic acids, stearyl fumarate, sucrose, tants, talc, tragacanth,
tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof. Excipients for
preparation of compositions comprising a compound of this invention having Formula (I) to
be stered ophthalmically or orally in liquid dosage forms include, for example,
1,3-butylene glycol, castor oil, corn oil, cottonseed oil, l, fatty acid esters of sorbitan,
germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene
glycol, sesame oil, water and mixtures thereof. Excipients for preparation of itions
comprising a compound of this invention having Formula (I) to be administered osmotically
e, for example, chlorofluorohydrocarbons, ethanol, water and mixtures thereof.
Excipients for preparation of compositions comprising a compound of this invention having
Formula (I) to be administered erally include, for example, 1,3-butanediol, castor oil,
corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil,
peanut oil, 's on, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium
chloride solution, water and mixtures f. Excipients for preparation of compositions
comprising a compound of this invention having Formula (I) to be administered rectally or
vaginally include, for example, cocoa butter, polyethylene glycol, wax and mixtures f.
Compounds having Formula (I) are expected to be useful when used with alkylating
agents, angiogenesis inhibitors, dies, antimetabolites, antimitotics, antiproliferatives,
antivirals, aurora kinase inhibitors, other sis promoters (for example, Bcl-xL, Bcl-w
and Bfl-1) inhibitors, activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE
(Bi-Specific T cell Engager) antibodies, dy drug conjugates, biologic se
modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2
inhibitors, DVDs, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth
factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone ylase (HDAC)
inhibitors, hormonal therapies, immunologicals, inhibitors of inhibitors of apoptosis proteins
(IAPs), intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors,
mammalian target of rapamycin inhibitors, microRNA’s, mitogen-activated extracellular
signal-regulated kinase inhibitors, multivalent binding proteins, eroidal
nflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase
(PARP) inhibitors, platinum chemotherapeutics, polo-like kinase (Plk) inhibitors,
phosphoinositide-3 kinase (PI3K) inhibitors, proteosome inhibitors, purine analogs,
pyrimidine analogs, receptor tyrosine kinase inhibitors, ids/deltoids plant alkaloids,
small inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors, ubiquitin ligase
inhibitors, and the like, and in combination with one or more of these agents .
BiTE antibodies are bi-specific antibodies that direct T-cells to attack cancer cells by
simultaneously binding the two cells. The T-cell then attacks the target cancer cell.
es of BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab
(Micromet MT103) and the like. Without being limited by theory, one of the mechanisms by
which T-cells elicit apoptosis of the target cancer cell is by exocytosis of cytolytic granule
components, which include perforin and granzyme B.
SiRNAs are molecules having endogenous RNA bases or chemically modified
tides. The modifications do not abolish cellular activity, but rather impart increased
stability and/or increased ar potency. Examples of al modifications include
phosphorothioate groups, 2'-deoxynucleotide, 3-containing ribonucleotides, 2'-F-
ribonucleotides, hoxyethyl ribonucleotides, combinations thereof and the like. The
siRNA can have varying lengths (e.g., 10-200 bps) and structures (e.g., hairpins,
single/double strands, bulges, nicks/gaps, ches) and are processed in cells to e
active gene silencing. A double-stranded siRNA (dsRNA) can have the same number of
nucleotides on each strand (blunt ends) or tric ends (overhangs). The ng of 1-2
nucleotides can be present on the sense and/or the antisense strand, as well as present on the
'- and/ or the 3'-ends of a given strand. For example, siRNAs targeting Mcl-1 have been
shown to enhance the activity of ABT-263, (i.e., N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-
1-cyclohexenyl)methyl)piperazinyl)benzoyl)(((1R)(morpholinyl)
((phenylsulfanyl)methyl)propyl)amino)((trifluoromethyl)sulfonyl)benzenesulfonamide) or
ABT-737 (i.e., N-(4-(4-((4'-chloro(1,1'-biphenyl)yl)methyl)piperazinyl)benzoyl)
(((1R)(dimethylamino)((phenylsulfanyl)methyl)propyl)amino)
nitrobenzenesulfonamide) in multiple tumor cell lines (Tse et. al, Cancer Research 2008,
68(9), 3421 and references therein).
Multivalent binding proteins are binding proteins sing two or more antigen
binding sites. Multivalent binding proteins are engineered to have the three or more antigen
binding sites and are generally not naturally occurring antibodies. The term “multispecific
binding n” means a binding protein capable of binding two or more d or unrelated
targets. Dual variable domain (DVD) binding proteins are tetravalent or multivalent binding
proteins binding proteins comprising two or more antigen binding sites. Such DVDs may be
monospecific (i.e., capable of binding one antigen) or multispecific (i.e., capable of g
two or more antigens). DVD binding proteins comprising two heavy chain DVD
ptides and two light chain DVD ptides are referred to as DVD Ig's. Each half of
a DVD Ig ses a heavy chain DVD polypeptide, a light chain DVD polypeptide, and
two n binding sites. Each g site comprises a heavy chain variable domain and a
light chain variable domain with a total of 6 CDRs involved in antigen binding per antigen
binding site.
Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,
bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU), chlorambucil,
CLORETAZINE® (laromustine, VNP ), cyclophosphamide, decarbazine,
estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU),
mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide,
ranimustine, temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, rofosfamide
and the like.
Angiogenesis inhibitors include elial-specific receptor tyrosine kinase (Tie-2)
inhibitors, epidermal growth factor or (EGFR) inhibitors, insulin growth -2
receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix
metalloproteinase-9 (MMP-9) tors, platelet-derived growth factor receptor (PDGFR)
inhibitors, thrombospondin analogs, vascular endothelial growth factor receptor ne
kinase (VEGFR) inhibitors and the like.
tabolites e ALIMTA® (pemetrexed disodium, 14, MTA),
-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine), clofarabine,
cytarabine, cytarabine ocfosfate, cytosine arabinoside, decitabine, deferoxamine,
doxifluridine, eflornithine, EICAR (5-ethynylE -D-ribofuranosylimidazole
carboxamide), enocitabine, cytidine, fludarabine, 5-fluorouracil alone or in combination
with leucovorin, GEMZAR® tabine), hydroxyurea, N®(melphalan),
mercaptopurine, 6-mercaptopurine riboside, rexate, mycophenolic acid, nelarabine,
nolatrexed, ocfosfate, exol, pentostatin, raltitrexed, Ribavirin, triapine, trimetrexate, S-1,
tiazofurin, tegafur, TS-1, vidarabine, UFT and the like.
Antivirals include ritonavir, hydroxychloroquine and the like.
Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680, Aurora
A-specific kinase inhibitors, Aurora B-specific kinase inhibitors and pan-Aurora kinase
inhibitors and the like.
Bcl-2 protein inhibitors include AT-101 ((-)gossypol), GENASENSE® (G3139 or
oblimersen (Bcltargeting antisense oligonucleotide)), IPI-194, IPI-565, N-(4-(4-((4'-
chloro(1,1'-biphenyl)yl)methyl)piperazinyl)benzoyl)(((1R)(dimethylamino)
((phenylsulfanyl)methyl)propyl)amino)nitrobenzenesulfonamide) (ABT-737), N-(4-(4-((2-
(4-chlorophenyl)-5,5-dimethylcyclohexenyl)methyl)piperazinyl)benzoyl)
(((1R)(morpholinyl)((phenylsulfanyl)methyl)propyl)amino)
((trifluoromethyl)sulfonyl)benzenesulfonamide (ABT-263), GX-070 (obatoclax) and the like.
Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC®
(imatinib) and the like.
CDK inhibitors e AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,
flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202,
R-roscovitine), ZK-304709 and the like.
COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®
(valdecoxib), BMS347070, CELEBREX® oxib), COX-189 (lumiracoxib), CT-3,
DERAMAXX® (deracoxib), JTE-522, 4-methyl(3,4-dimethylphenyl)(4-
sulfamoylphenyl-1H-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067,
SC-58125, SD-8381, SVT-2016, S-2474, T-614, VIOXX® (rofecoxib) and the like.
EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF-vaccine,
EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA® inib),
A® inib or OSI-774), TP-38, EGFR fusion protein, TYKERB® (lapatinib) and
the like.
ErbB2 receptor inhibitors include CP714, 3 (canertinib), HERCEPTIN®
(trastuzumab), TYKERB® (lapatinib), RG® (2C4, petuzumab), 5,
GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine),
APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific antibody, B7.her2IgG3, AS HER2
ctional bispecfic antibodies, mAB AR-209, mAB 2B-1 and the like.
Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, in,
suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid and the like.
HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024,
G, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (human recombinant antibody
to HSP-90), NCS-683664, PU24FCl, PU-3, radicicol, 12, STA-9090 09 and
the like.
Inhibitors of inhibitors of apoptosis proteins e HGS1029, GDC-0145, GDC-
0152, LCL-161, LBW-242 and the like.
dy drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE,
anti-CD22-MCC-DM1, CRvcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35,
SGN-75 and the like
tors of death receptor pathway include TRAIL, antibodies or other agents that
target TRAIL or death receptors (e.g., DR4 and DR5) such as Apomab, conatumumab, ETR2-
ST01, GDC0145 (lexatumumab), HGS-1029, LBY-135, PRO-1762 and trastuzumab.
Kinesin inhibitors e Eg5 inhibitors such as AZD4877, ARRY-520; CENPE
inhibitors such as GSK923295A and the like.
JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and INCB018424 and the
like.
MEK inhibitors include ARRY-142886, 38162 PD-325901, PD-98059 and
the like.
mTOR inhibitors include AP-23573, CCI-779, imus, 1, rapamycin,
temsirolimus, ATP-competitive TORC1/TORC2 inhibitors, including PI-103, PP242, PP30,
Torin 1 and the like.
Non-steroidal nflammatory drugs e AMIGESIC® (salsalate), DOLOBID®
(diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen), RELAFEN® (nabumetone),
FELDENE® (piroxicam), ibuprofen cream, ALEVE® (naproxen) and NAPROSYN®
(naproxen), VOLTAREN® (diclofenac), INDOCIN® (indomethacin), CLINORIL® (sulindac),
TOLECTIN® (tolmetin), LODINE® (etodolac), TORADOL® (ketorolac), DAYPRO®
(oxaprozin) and the like.
PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.
Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin) eptaplatin,
lobaplatin, nedaplatin, PARAPLATIN® (carboplatin), satraplatin, picoplatin and the like.
ike kinase inhibitors e BI-2536 and the like.
Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin, LY294002, XL-
147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866, 41, BGT226, BEZ235,
XL765 and the like.
Thrombospondin analogs include ABT-510, 7, ABT-898, TSP-1 and the like.
VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788,
YME™ (a me that inhibits angiogenesis (Ribozyme Pharmaceuticals
er, CO.) and , (Emeryville, CA)) , axitinib (AG-13736), AZD-2171,
CP-547,632, IM-862, MACUGEN (pegaptamib), NEXAVAR® (sorafenib, BAY43-9006),
pazopanib 6034), vatalanib (PTK-787, ZK-222584), SUTENT® (sunitinib, SU-
11248), VEGF trap, ZACTIMA™ tanib, ZD-6474) and the like.
Antibiotics include intercalating antibiotics aclarubicin, actinomycin D, amrubicin,
annamycin, adriamycin, BLENOXANE® ycin), daunorubicin, CAELYX® or
MYOCET® (liposomal doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS®
(idarubicin), mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin,
amycin, stimalamer, streptozocin, VALSTAR® (valrubicin), zinostatin and the like.
omerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide,
amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR® (irinotecan hydrochloride),
camptothecin, CARDIOXANE® (dexrazoxine), diflomotecan, edotecarin, ELLENCE® or
PHARMORUBICIN® (epirubicin), etoposide, exatecan, 10-hydroxycamptothecin, gimatecan,
lurtotecan, mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38,
tafluposide, topotecan and the like.
Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies, chTNT-
1/B, mab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab), IGF1R-specific
antibodies, lintuzumab, X® (edrecolomab), RENCAREX® (WX G250),
RITUXAN® (rituximab), ticilimumab, trastuzimab, CD20 antibodies types I and II and the
like.
Hormonal ies include ARIMIDEX® (anastrozole), AROMASIN® (exemestane),
arzoxifene, CASODEX® (bicalutamide), CETROTIDE® (cetrorelix), degarelix, deslorelin,
DESOPAN® stane), dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene),
AFEMA™ (fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®
(letrozole), tane, glucocorticoids, HECTOROL® (doxercalciferol), RENAGEL®
(sevelamer carbonate), lasofoxifene, leuprolide acetate, MEGACE® (megesterol),
MIFEPREX® (mifepristone), NILANDRON™ (nilutamide), NOLVADEX® (tamoxifen
citrate), IS™ (abarelix), sone, PROPECIA® (finasteride), rilostane,
SUPREFACT® (buserelin), TRELSTAR® (luteinizing hormone releasing e (LHRH)),
VANTAS® (Histrelin implant), VETORYL® (trilostane or modrastane), X®
(fosrelin, goserelin) and the like.
ds and retinoids include seocalcitol (EB1089, CB1093), lexacalcitrol
(KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN® (liposomal tretinoin),
TARGRETIN® (bexarotene), LGD-1550 and the like.
PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436, AZD-2281, AG-
014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.
Plant alkaloids include, but are not limited to, stine, vinblastine, vindesine,
vinorelbine and the like.
Proteasome inhibitors include VELCADE® (bortezomib), MG132, 52, PR-171
and the like.
Examples of immunologicals include interferons and other immune-enhancing
agents. Interferons e interferon alpha, interferon alpha-2a, interferon alpha-2b,
interferon beta, interferon gamma-1a, ACTIMMUNE® (interferon gamma-1b) or interferon
gamma-n1, combinations thereof and the like. Other agents include ALFAFERONE® ,(IFN-
D), BAM-002 (oxidized glutathione), BEROMUN® (tasonermin), BEXXAR® (tositumomab),
CAMPATH® (alemtuzumab), CTLA4 oxic lymphocyte antigen 4), decarbazine,
denileukin, epratuzumab, YTE® (lenograstim), lentinan, leukocyte alpha eron,
imiquimod, MDX-010 (anti-CTLA-4), melanoma vaccine, mab, molgramostim,
MYLOTARG™ zumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC-CL,
® (oregovomab), pemtumomab (Y-muHMFG1), PROVENGE® (sipuleucel-T),
amostim, sizofilan, teceleukin, THERACYS® (Bacillus Calmette-Guerin), ubenimex,
VIRULIZIN® (immunotherapeutic, Lorus Pharmaceuticals), Z-100 (Specific Substance of
Maruyama (SSM)), WF-10 (Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin),
ZADAXIN® (thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-Ibritumomab
tiuxetan) and the like.
ical response ers are agents that modify defense mechanisms of living
sms or ical responses, such as survival, growth or differentiation of tissue cells to
direct them to have anti-tumor activity and include krestin, lentinan, sizofiran, picibanil PF-
3512676 (CpG-8954), ubenimex and the like.
Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosine arabinoside,
doxifluridine, FLUDARA® (fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR®
(gemcitabine), TOMUDEX® (ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and
the like.
Purine analogs include LANVIS® uanine) and PURI-NETHOL®
(mercaptopurine).
Antimitotic agents include batabulin, epothilone D (KOS-862), N-(2-((4-
hydroxyphenyl)amino)pyridinyl)methoxybenzenesulfonamide, ixabepilone (BMS
247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940 (109881), patupilone, XRP-9881
(larotaxel), vinflunine, ZK-EPO (synthetic epothilone) and the like.
Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins, NEDD8
inhibitors such as MLN4924 and the like.
Compounds of this invention can also be used as radiosensitizers that enhance the
efficacy of herapy. Examples of radiotherapy include external beam radiotherapy,
teletherapy, brachytherapy and sealed, unsealed source radiotherapy and the like.
Additionally, compounds having Formula (I) may be combined with other
chemotherapeutic agents such as NE™ (ABI-007), ABT-100 (farnesyl transferase
inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® or MEVACOR® (lovastatin),
AMPLIGEN® (poly I:poly C12U, a synthetic RNA), APTOSYN® (exisulind), AREDIA®
(pamidronic acid), arglabin, L-asparaginase, atamestane hyl-3,17-dione-androsta-1,4-
diene), AVAGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2 (mitumomab),
tin or cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC® (cancer
vaccine), ® leukin), CEPLENE® (histamine dihydrochloride), CERVARIX®
(human papillomavirus vaccine), CHOP® (C: N® (cyclophosphamide); H:
YCIN® (hydroxydoxorubicin); O: stine IN®);P: sone),
CYPAT™ (cyproterone e), statin A4P, DAB(389)EGF (catalytic and
translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal
growth factor) or TransMID-107R™ (diphtheria toxins), dacarbazine, dactinomycin, 5,6-
dimethylxanthenoneacetic acid (DMXAA), eniluracil, EVIZON™ (squalamine lactate),
DIMERICINE® (T4N5 liposome lotion), discodermolide, DX-8951f (exatecan mesylate),
enzastaurin, EPO906 (epithilone B), GARDASIL® (quadrivalent human papillomavirus
(Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®, GMK
(ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine), halofuginone, histerelin,
hydroxycarbamide, ibandronic acid, IGN-101, ILPE38, ILPE38QQR (cintredekin
besudotox), ILpseudomonas exotoxin, interferon-α, interferon-γ, JUNOVAN™ or
MEPACT™ (mifamurtide), lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine
(hexadecylphosphocholine), NEOVASTAT®(AE-941), NEUTREXIN® (trimetrexate
glucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme),
ONCOPHAGE® oma vaccine treatment), ONCOVAX® (IL-2 e),
ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb
(murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponins from ginseng
comprising 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol (aPPT)), panitumumab,
PANVAC®-VF (investigational cancer vaccine), pegaspargase, PEG Interferon A,
odiol, procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID®
(lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide), ANE®
(acitretin), staurosporine (Streptomyces staurospores), talabostat (PT100), TARGRETIN®
(bexarotene), TAXOPREXIN® aclitaxel), TELCYTA® (canfosfamide, TLK286),
temilifene, TEMODAR® (temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-
KLH), thymitaq (2-amino-3,4-dihydromethyloxo(4-pyridylthio)quinazoline
ochloride), TNFERADE™ (adenovector: DNA carrier containing the gene for tumor
necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan), tretinoin (Retin-A), tetrandrine,
TRISENOX® (arsenic trioxide), VIRULIZIN®, ukrain ative of alkaloids from the
greater celandine plant), vitaxin(anti-alphavbeta3 antibody), XCYTRIN® (motexafin
gadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel umex), YONDELIS®
(trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ® (zolendronic acid),
cin and the like.
Data
ination of the utility of nds having Formula (I) as s to and
inhibitors of anti-apoptotic Bcl-xL ns was performed using the Time Resolved-
Fluorescence Resonance Energy Transfer (TR-FRET) Assay. Tb-anti-GST antibody was
purchased from Invitrogen (Catalog No. PV4216).
Probe Synthesis
All reagents were used as ed from the vendor unless otherwise ied.
Peptide synthesis reagents including diisopropylethylamine (DIEA), dichloromethane (DCM),
N-methylpyrrolidone (NMP), 2-(1H-benzotriazoleyl)-1,1,3,3-tetramethyluronium
hexafluorophosphate , N-hydroxybenzotriazole (HOBt) and piperidine were obtained
from Applied Biosystems, Inc. (ABI), Foster City, CA or American Bioanalytical, Natick,
MA. Preloaded 9-Fluorenylmethyloxycarbonyl (Fmoc) amino acid cartridges (Fmoc-Ala-
OH, Fmoc-Cys(Trt)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Phe-OH, Fmoc-
Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Met-
OH, Fmoc-Asn(Trt)-OH, Fmoc-Pro-OH, Fmor-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-
Ser(tBu)-OH, hr(tBu)-OH, Fmoc-Val-OH, rp(Boc)-OH, Fmoc-Tyr(tBu)-OH)
were obtained from ABI or Anaspec, San Jose, CA. The peptide sis resin (Fmoc-Rink
amide MBHA resin) and Fmoc-Lys(Mtt)-OH were obtained from Novabiochem, San Diego,
CA. Single-isomer 6-carboxyfluorescein imidyl ester (6-FAM-NHS) was obtained
from Anaspec. Trifluoroacetic acid (TFA) was obtained from Oakwood Products, West
Columbia, SC. Thioanisole, phenol, triisopropylsilane (TIS), 3,6-dioxa-1,8-octanedithiol
(DODT) and isopropanol were obtained from Aldrich Chemical Co., Milwaukee, WI.
Matrix-assisted laser desorption ionization mass-spectra (MALDI-MS) were recorded on an
Applied Biosystems Voyager DE-PRO MS). Electrospray pectra (ESI-MS) were
recorded on Finnigan SSQ7000 (Finnigan Corp., San Jose, CA) in both positive and negative
ion mode.
General Procedure For Phase Peptide Synthesis (SPPS)
Peptides were synthesized with, at most, 250 μmol preloaded Wang resin/vessel on
an ABI 433A peptide synthesizer using 250 μmol scale Fastmoc™ coupling cycles. Preloaded
cartridges containing 1 mmol standard Fmoc-amino acids, except for the position of
attachment of the phore, where 1 mmol Fmoc-Lys(Mtt)-OH was placed in the cartridge,
were used with conductivity feedback ring. N-terminal acetylation was accomplished
by using 1 mmol acetic acid in a cartridge under standard coupling conditions.
Removal Of 4-Methyltrityl (Mtt) From Lysine
The resin from the synthesizer was washed thrice with DCM and kept wet. 150 mL of
95:4:1 dichloromethane:triisopropylsilane:trifluoroacetic acid was flowed h the resin
bed over 30 minutes. The mixture turned deep yellow then faded to pale yellow. 100 mL of
DMF was flowed through the bed over 15 minutes. The resin was then washed thrice with
DMF and filtered. rin tests showed a strong signal for primary amine.
Resin Labeling With 6-Carboxyfluorescein-NHS (6-FAM-NHS)
The resin was treated with 2 equivalents NHS in 1% DIEA/DMF and stirred
or shaken at t temperature overnight. When complete, the resin was drained, washed
thrice with DMF, thrice with (1× DCM and 1× methanol) and dried to provide an orange resin
that was negative by ninhydrin test.
General Procedure For Cleavage And Deprotection Of Resin-Bound e
Peptides were cleaved from the resin by shaking for 3 hours at ambient temperature in
a cleavage cocktail consisting of 80% TFA, 5% water, 5% thioanisole, 5% phenol, 2.5% TIS,
and 2.5% EDT (1 mL/0.1 g . The resin was removed by filtration and rinsing twice with
TFA. The TFA was evaporated from the filtrates, and product was precipitated with ether (10
mL/0.1 g resin), recovered by centrifugation, washed twice with ether (10 mL/0.1 g resin) and
dried to give the crude peptide.
General Procedure For Purification Of Peptides
The crude peptides were purified on a Gilson preparative HPLC system running
Unipoint analysis software (Gilson, Inc., Middleton, WI) on a radial compression column
containing two 25 u 100 mm segments packed with Delta-Pak C18 15 μm particles with
100 Å pore size and eluted with one of the gradient methods listed below. One to two
milliliters of crude e solution (10 mg/mL in 90% DMSO/water) was purified per
injection. The peaks containing the product(s) from each run were pooled and lyophilized.
All preparative runs were run at 20 mL/min with eluents as buffer A: 0.1% ter and
buffer B: acetonitrile.
General Procedure For Analytical HPLC
Analytical HPLC was performed on a Hewlett-Packard 1200 series system with a
array detector and a Hewlett-Packard 1046A fluorescence detector running HPLC 3D
ChemStation software version A.03.04 (Hewlett-Packard. Palo Alto, CA) on a 4.6 u 250 mm
YMC column packed with ODS-AQ 5 μm particles with a 120 Å pore size and eluted with
one of the gradient methods listed below after preequilibrating at the starting conditions for 7
minutes. s were buffer A: 0.1% TFA-water and buffer B: acetonitrile. The flow rate
for all gradients was 1 mL/min.
F-Bak: Peptide Probe -(SEQ ID NO: 1)GQVGRQLAIIGDK(6-FAM)-(SEQ ID NO:
2)INR-NH2
Fmoc-Rink amide MBHA resin was ed using the l peptide synthesis
procedure to provide the protected resin-bound e (1.020 g). The Mtt group was
d, labeled with 6-FAM-NHS and d and deprotected as bed hereinabove to
e the crude product as an orange solid (0.37 g). This product was purified by RPHPLC.
Fractions across the main peak were tested by analytical RP-HPLC, and the pure
fractions were isolated and lized, with the major peak providing the title compound
(0.0802 g) as a yellow solid; MALDI-MS m/z = 2137.1 [(M+H)+].
Alternative Synthesis of Peptide Probe F-Bak: Acetyl-(SEQ ID NO:
1)GQVGRQLAIIGDK(6-FAM)-(SEQ ID NO:2)INR-NH2
The protected peptide was assembled on 0.25 mmol Fmoc-Rink amide MBHA resin
(Novabiochem) on an Applied Biosystems 433A automated peptide synthesizer running
Fastmoc coupling cycles using pre-loaded 1 mmol amino acid cartridges, except for the
fluorescein(6-FAM)-labeled lysine, where 1 mmol Fmoc-Lys(4-methyltrityl) was weighed
into the cartridge. The N-terminal acetyl group was incorporated by putting 1 mmol acetic
acid in a cartridge and coupling as described hereinabove. Selective removal of the 4-
methyltrityl group was accomplished with a on of 95:4:1 DCM:TIS:TFA (v/v/v) flowed
through the resin over 15 minutes, followed by quenching with a flow of dimethylformamide.
Single-isomer 6-carboxyfluorescein-NHS was reacted with the lysine side-chain in 1% DIEA
in DMF and confirmed complete by ninhydrin testing. The peptide was cleaved from the
resin and side-chains deprotected by treating with 80:5:5:5:2.5:2.5 ter/phenol/
thioanisole/triisopropylsilane: 3,6-dioxa-1,8-octanedithiol /v/v/v), and the crude peptide
was recovered by precipitation with diethyl ether. The crude peptide was purified by reversephase
erformance liquid chromatography, and its purity and identity were confirmed by
analytical reverse-phase high-performance liquid chromatography and matrix-assisted laserdesorption
mass-spectrometry (m/z = 2137.1 ((M+H)+).
Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) Assay
The ement of competitionof compounds of Formula (I)with F-Bakfor a Bcl-
2 family protein (Bcl-xL) binding site using a Time Resolved Fluorescence nce
Energy Transfer (TR-FRET) binding assay:
Test compounds were serially diluted in DMSO starting at 50 PM (2x starting
concentration; 10% DMSO) and 10 PL transferred into a ll plate. Then 10 PL of a
protein/probe/antibody mix is added to each well at final concentrations listed in Table 1.
Table 1
Protein Probe Protein Probe dy Antibody
(nM) (nM) (nM)
GST-Bcl- F-Bak (GQVGRQLAIIGDK(6- 1 100 Tb-anti- 1
xL FAM)INR-amide) GST
The samples are then mixed on a shaker for 1 minute then ted for an additional
2 hours at room ature. For each assay plate, a probe/antibody and
protein/antibody/probe mixture were included as a negative and a ve l,
respectively. scence was measured on the Envision (Perkin Elmer) using a 340/35 nm
excitation filter and 520/525 (F-Bak) and 495/510 nm (Tb-labeled anti-his antibody) emission
filters. Dissociation constants (Ki) were determined using Wang's equation (Wang, Z.X. An
exact mathematical expression for describing competitive binding of two ent ligands to a
protein molecule. FEBS Lett. 1995 360:111-114). The TR-FRET assay can be performed in
the presence of varying concentrations of human serum (HS) or fetal bovine serum (FBS).
TR-FRET assay results (Ki in nanomolar) for representative compounds of a (I) are
provided below in Table 2.
For comparison, the measurement of the competition of compounds of Formula (I)
for other Bcl-2 family protein binding sites (e.g., Bcl-2) using the TR-FRET binding assay
was accomplished by tuting GST-Bcl-xL in the TR-FRET assay with other GST-labeled
protein, e.g., GST-Bcl-2, prepared se.
In one embodiment, compounds of Formula (I) selectively inhibit the Bcl-2 family
protein, Bcl-xL, over other Bcl-2 family proteins, such as Bcl-2. For comparison, data (Ki in
micromolar) from the measurement of the competition by certain compoundsofFormula (I)
(i.e., Examples 20, 43, 49, 82, 99, 107, 117, 130, 134, 148 159, 176 and 185 in Table 3) with
F-Bak for the Bcl-2 g site using the TR-FRET binding assay are 0.070, 0.023, 0.039,
0.033, 0.033, 0.056, 0.021, 0.076, 0.024, 0.075, 0.272, 0.177 and 0.014, respectively.
FL5.12 Cellular Assay
The efficacy of the nds of Formula (I) can also be determined in cell-based
killing assays using a variety of cell lines and mouse tumor models. For example, their
activity on cell viability can be assessed on a panel of cultured tumorigenic and nontumorigenic
cell lines, as well as primary mouse or human cell populations. In one exemplary
set of conditions, mouse FL5.12 cells transfected with Bcl-XL were cultured under standard
conditions in RPMI with 2 mM glutamine, 1% 100 mM sodium pyruvate, 2% 1 M HEPES, 4
μL/L of β-mercaptoethanol, 1% penicillin−streptomycin, 10% FBS, and 10% WEHI-3B
conditioned media (for IL-3). For assaying the compound activity, the cells were ged
into an ILdepleted deprivation media, which was identical to the growth media except for
the absence of FBS and WEHI-3B conditional media, for 2 days. Then the cells were
exchanged to 3% FBS assay media (RPMI with 2 mM glutamine, 1% 100 mM sodium
te, 2% 1 M HEPES, 4 μL/L of β-mercaptoethanol, 1% penicillin−streptomycin, 3%
FBS). Compounds in series dilutions were added, and the cells were cultured for 24 hours.
Compounds in series dilutions were added, and the cells were ed for 24 hours. Cell
viability was d using the the CellTiter-Glo assay (Promega Corp., Madison, WI)
according to the manufacturer instructions. Individual determinations were the result of
duplicate values. Cell viability assay results (EC50 in lar) for representative
compounds are provided below in Table 2.
Table 2. In Vitro Data
TR-FRET binding FL5.12 Bcl-xL,- TR-FRET g FL5.12 Bcl-xL,-
EX EX
Bcl-xL Ki (nM) IL3, EC 50 (nM) Bcl-xL Ki (nM) IL3, EC50 (nM)
1 12 425 95 11 542
2 205 n.d. 96 12 620
3 258 >1000 97 2 <1
4 115 n.d. 98 2 421
19 408 99 0.9 60
6 >1000 n.d. 100 3 66
7 312 n.d. 101 0.4 <1
8 98 n.d. 102 <0.1 n.d.
9 6 378 103 0.6 >1000
68 n.d. 104 14 >1000
11 180 >1000 105 7 >1000
12 8 51 106 0.1 234
13 12 498 107 0.2 10
14 12 >1000 108 9 >1000
35 >1000 109 49 >1000
16 159 n.d. 110 0.3 90
17 31 >1000 111 21 >1000
18 38 621 112 0.7 523
19 28 398 113 19 >1000
2 13 114 0.2 220
21 183 >1000 115 5 916
22 6 214 116 <0.1 667
23 182 >1000 117 <0.1 131
24 64 >1000 118 0.2 361
8 377 119 <0.1 762
26 167 >1000 120 0.4 859
27 315 >1000 121 0.1 82
28 33 >1000 122 117 >1000
29 18 >1000 123 <0.1 16
2 298 124 <0.1 57
31 18 >1000 125 0.3 527
32 5 216 126 47 >1000
33 169 >1000 127 2 >1000
34 23 907 128 7 >1000
91 n.d. 129 <0.1 18
36 8 >1000 130 <0.1 30
37 17 347 131 <0.1 9
38 48 >1000 132 3 n.d.
39 56 >1000 133 0.9 n.d.
40 16 570 134 <0.1 0.9
41 1 11 135 78 >1000
42 2 233 136 1.4 >1000
43 0.9 4 137 1.5 363
44 17 >1000 138 <0.1 >1000
45 19 >1000 139 0.4 >1000
46 9 >1000 140 2.3 >1000
47 16 881 141 1 433
48 7 >1000 142 0.5 >1000
49 0.6 12 143 <0.1 19
50 99 >1000 144 <0.1 213
51 122 >1000 145 <0.1 0.2
52 18 570 146 <0.1 11
53 14 387 147 <0.1 1
54 15 501 148 <0.1 13
55 18 317 149 0.3 986
56 24 583 150 0.2 339
57 14 741 151 <0.1 0.6
58 174 >1000 152 <0.1 1
59 424 >1000 153 0.3 587
60 5 219 154 <0.1 15
61 11 380 155 <0.1 7
62 61 >1000 156 0.2 15
63 2 27 157 <0.1 0.3
64 61 >1000 158 <0.1 364
65 393 >1000 159 0.2 31
66 3 60 160 <0.1 14
67 7 106 161 <0.1 7
68 279 >1000 162 <0.1 5
69 91 >1000 163 0.4 211
70 5 58 164 <0.1 308
71 18 n.d. 165 <0.1 9
72 28 >1000 166 <0.1 30
73 0.9 8 167 <0.1 81
74 6 335 168 <0.1 14
75 28 919 169 <0.1 10
76 29 >1000 170 <0.1 0.5
77 10 431 171 <0.1 97
78 379 >1000 172 <0.1 1
79 0.5 19 173 <0.1 0.1
80 4 253 174 <0.1 210
81 0.6 37 175 <0.1 33
82 0.5 8 176 <0.1 10
83 0.5 >1000 177 <0.1 24
84 0.7 12 178 <0.1 0.2
84 0.7 12 179 <0.1 6
85 2 <1 180 <0.1 <0.1
86 2 4 181 <0.1 241
87 4 124 182 0.2 6
88 3 229 183 0.7 507
89 0.5 23 184 <0.1 2
90 1 n.d. 185 <0.1 n.d.
91 0.9 30 186 <0.1 n.d.
92 2 56 187 0.4 318
93 16 295 188 0.5 546
94 5 253
EX = Example, n.d. = no data available
Molt-4 Cellular Assay
Molt-4 (ATCC, Manassas, VA) human acute lymphoblastic leukemia cells were
plated 50,000 cells per well in 96-well tissue e plates in a total volume of 100 PL tissue
culture medium supplemented with 10% human serum (Invitrogen, ad, CA) and treated
with a 3-fold serial dilution of the compounds of interest from 5 PM to 0.020 PL. Each
concentration was tested in duplicate at least 3 separate times. The number of viable cells
following 48 hours of compound treatment was determined using the CellTiter 96® Aqueous
non-radioactive cell proliferation MTS assay according to manufacturer's recommendations
(Promega Corp., Madison, WI). Molt-4 cell viability results (i.e. EC50 in micromolar) for
certain compounds of Formula (I), (i.e.,Examples 81, 82, 84, 87, 124, 130, 134, 145, 151,
152, 166, 179, and 186 in Table 2), are 0.33, 0.135, 0.501, 1.2, 2.7, 0.532, 0.029, 0.081,
0.014, 0.006, 0.586, 0.493, and 0.006, respectively.
Single Dose Pharmacokinetics
The single dose pharmacokinetics of select compounds were evaluated in
Sprague−Dawley rats (Charles River) after a 5 mg/kg oral dose (n = 3) (10% DMSO in PEG-
400) administered by gavage or by 5 mg/kg IV bolus dose (n = 3) (10% DMSO in PEG-400).
Compound and the internal standard were separated from each other and coextracted
contaminants on a 50 mm × 3 mm Keystone Betasil CN 5 μm column with an
acetonitrile/0.1% trifluoroacetic acid mobile phase (50:50, by volume) at a flow rate of 0.7
mL/min. Analysis was performed on a Sciex API3000 biomolecular mass analyzer with a
heated nebulizer interface. Compound and internal standard peak areas were ined using
Sciex MacQuan software. The plasma drug tration of each sample was ated by
least-squares linear regression analysis (nonweighted) of the peak area ratio (parent/internal
rd) of the spiked plasma standards versus concentration. The plasma concentration data
were ted to multiexponential curve g using WinNonlin.3. The area under the
plasma concentration−time curve was calculated using the linear trapezoidal rule for the
plasma concentration−time profiles.
In pharmacology, bioavailability (BA) is a egory of tion and is used to
describe the fraction of an administered dose of unchanged drug that reaches the systemic
circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a
medication is administered intravenously, its bioavailability is 100 % (see Griffin, J.P. The
ok of Pharmaceutical Medicine (6th Ed.). New Jersey: BMJ Books). However, when a
medication is administered via other routes (such as orally), its bioavailability generally
decreases (due to incomplete absorption and first-pass lism) and may vary from patient
to patient. Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability
must be considered when calculating dosages for non-intravenous routes of administration.
One way to calculate bioavailability of a drug or agent is by dividing the plasma
concentration following an oral dose by the concentration following an intravenous dose dose.
The oral bioavailability (as represented by % F) in Sprague-Dawley rats for representative
compounds of the invention are provided below in Table 3.
In the drug discovery setting, it is lly accepted that Lipinski’s “rule of 5”
ts that poor oral tion or poor permeation is likely when two or more of the
following metrics are satisfied: i) there are more than 5 hydrogen bond donors, ii) the
molecular weight is greater than 500, iii) there are greater than 10 hydrogen bond acceptors
(expressed as the sum of nitrogen and oxygen atoms), or iv) the calculated Log P (cLogP) is
greater than 5 (Lipinski et al. Adv. Drug Del. Rev. 2001, 3-26). Indeed, the combination of
high molecular weight (>500) and high cLogP (>5) is the best predictor of poor tion or
permeation. Compounds described herein generally exceed the recommended ranges
pertaining to molecular weight (>500) and cLogP (>5), as shown in Table 3. It is notable,
therefore, that Examples described herein have acceptable oral ilability in rats (as
defined by % F > 10, see Martin J. Med. Chem. 2005, 48, 3164), as illustrated in Table 3.
Table 3. PK Data, Rat p.o. dose
Molecular F (%),
EXAMPLE # cLogP
weight dose
600.7 6.6 19, 5 mpk
12 614.7 6.7 29, 5 mpk
19 600.7 6.5 22, 5 mpk
600.7 6.5 17, 5 mpk
22 656.8 6.1 27, 5 mpk
23 572.6 6.5 20, 5 mpk
621.1 7.0 24,5 mpk
37 612.7 6.7 29, 5 mpk
63 592.7 6.8 20, 5 mpk
70 632.8 7.8 21, 5 mpk
73 642.7 6.8 19, 5 mpk
74 660.7 7.3 23, 5 mpk
82 620.8 7.9 45, 5 mpk
88 650.8 7.0 23, 5 mpk
89 674.8 6.3 13, 5 mpk
90 664.8 7.2 44, 5 mpk
91 616.7 7.2 16, 5 mpk
93 644.7 6.4 33, 5 mpk
97 678.8 7.7 33, 5 mpk
99 714.8 6.7 19, 5 mpk
101 680.8 6.7 40, 5 mpk
103 598.7 8.4 39, 5 mpk
106 596.7 8.4 24, 5 mpk
107 616.8 9.6 14, 5 mpk
110 612.7 8.6 36, 5 mpk
114 618.7 8.6 38, 5 mpk
119 622.7 8.4 54, 5 mpk
122 587.7 5.8 40,5 mpk
129 624.7 7.0 17, 5 mpk
130 630.6 7.8 32, 5 mpk
131 713.9 6.0 11, 5 mpk
134 678.9 8.0 50, 5 mpk
146 692.9 8.4 16, 5 mpk
147 692.9 8.5 37, 5 mpk
148 756.0 7.0 18, 5 mpk
151 694.9 7.5 30, 1 mpk
154 608.72 5.7 22, 1 mpk
156 625.8 8.8 39, 1 mpk
157 664.8 8.1 30, 1 mpk
Data in Table 2 and cited Molt-4 data show the utility of compounds of the ion
to functionally inhibit anti-apoptotic Bcl-xL protein in a cellular context. The ability of
compounds to kill FL5.12 cells over-expressing Bcl-xL or human tumor cell lines that are
dependant upon Bcl-xL such as Molt-4 cells is a direct measure of the compound’s ability to
inhibit anti-apoptotic Bcl-xL n function. Compounds of the invention are very effective
in killing FL5.12 cells over-expressing Bcl-xL or human tumor cell lines that are dependant
upon Bcl-xL such as Molt-4 cells as demonstrated by low EC50 values. In addition, as
demonstrated in Table 3, compounds of the invention have acceptable oral bioavailability in
preclinical rodent studies, and therefore may find utility as orally-dosed eutics in a
clinical setting.
Overexpression of Bcl-xL proteins correlates with resistance to chemotherapy,
clinical outcome, e ssion, l prognosis or a combination f in various
cancers and disorders of the immune system. Cancers include, but are not limited to,
hematologic and solid tumor types such as acoustic neuroma, acute ia, acute
lymphoblastic leukemia, acute myelogenous leukemia (monocytic, myeloblastic,
adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute tcell
leukemia, basal cell carcinoma, bile duct carcinoma, r , brain cancer, breast
cancer (including en-receptor positive breast cancer), bronchogenic carcinoma, Burkitt's
lymphoma, cervical cancer, chondrosarcoma, ma, choriocarcinoma, chronic leukemia,
chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic
myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma,
cystadenocarcinoma, dysproliferative changes (dysplasias and metaplasias), embryonal
carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma,
erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential
thrombocythemia, s tumor, fibrosarcoma, gastric carcinoma, germ cell ular
cancer, gestational trophobalstic disease, glioblastoma, head and neck cancer, heavy chain
disease, hemangioblastoma, hepatoma, cellular cancer, hormone insensitive prostate
cancer, leiomyosarcoma, liposarcoma, lung cancer (including small cell lung cancer and ll
cell lung cancer), ngioendothelio-sarcoma, lymphangiosarcoma, lymphoblastic
leukemia, lymphoma (lymphoma, including diffuse large B-cell lymphoma, follicular
lymphoma, Hodgkin’s lymphoma and non-Hodgkin’s lymphoma), malignancies and
hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate,
skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, medullary
carcinoma, medulloblastoma, melanoma, meningioma, elioma, multiple myeloma,
enous leukemia, myeloma, rcoma, neuroblastoma, oligodendroglioma, oral
cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary arcinomas,
papillary carcinoma, peripheral T-cell lymphoma, pinealoma, polycythemia vera, prostate
cancer (including hormone-insensitive (refractory) prostate cancer), rectal cancer, renal cell
carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma,
seminoma, skin cancer, small cell lung oma, solid tumors (carcinomas and sarcomas),
stomach cancer, squamous cell carcinoma, oma, sweat gland carcinoma, testicular
cancer (including germ cell ular cancer), thyroid cancer, Waldenström’s
macroglobulinemia, testicular tumors, uterine cancer, Wilms’ tumor and the like.
It is also expected that compounds having Formula (I) would inhibit growth of cells
expressing Bcl-xL proteins derived from a pediatric cancer or neoplasm ing embryonal
rhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatric acute myelogenous
leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic moma, pediatric
anaplastic large cell lymphoma, pediatric anaplastic medulloblastoma, pediatric atypical
teratoid/rhabdoid tumor of the central s system, pediatric biphenotypic acute leukemia,
pediatric Burkitts lymphoma, pediatric cancers of Ewing’s family of tumors such as primitive
neuroectodermal rumors, pediatric diffuse anaplastic Wilm’s tumor, pediatric favorable
histology Wilm’s tumor, ric glioblastoma, pediatric medulloblastoma, pediatric
neuroblastoma, pediatric lastoma-derived myelocytomatosis, pediatric pre-B-cell
cancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoid kidney tumor,
pediatric rhabdomyosarcoma, and pediatric T-cell cancers such as lymphoma and skin cancer
and the like.
Autoimmune disorders include ed deficiency disease syndrome
(AIDS), autoimmune lymphoproliferative syndrome, hemolytic anemia, inflammatory
diseases, and thrombocytopenia, acute or chronic immune disease ated with organ
transplantation, Addison's disease, allergic diseases, alopecia, alopecia areata, atheromatous
disease/arteriosclerosis, atherosclerosis, arthritis ding osteoarthritis, juvenile chronic
arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis and reactive tis), autoimmune
bullous disease, abetalipoprotemia, acquired immunodeficiency-related diseases, acute
immune disease ated with organ transplantation, acquired acrocyanosis, acute and
chronic parasitic or infectious processes, acute atitis, acute renal failure, acute
rheumatic fever, acute transverse myelitis, adenocarcinomas, aerial ectopic beats, adult
(acute) respiratory distress syndrome, AIDS dementia complex, lic cirrhosis, alcoholinduced
liver injury, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact
dermatitis, allergic rhinitis, allergy and asthma, allograft rejection, alpha-l- antitrypsin
deficiency, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, angina is,
ankylosing spondylitis associated lung disease, anterior horn cell degeneration, dy
ed cytotoxicity, antiphospholipid syndrome, anti-receptor hypersensitivity reactions,
aortic and peripheral aneurysms, aortic dissection, al hypertension, osclerosis,
arteriovenous fistula, arthropathy, asthenia, asthma, ataxia, atopic allergy, atrial fibrillation
(sustained or paroxysmal), atrial flutter, atrioventricular block, atrophic autoimmune
hypothyroidism, autoimmune haemolytic anaemia, mune hepatitis, type-1 autoimmune
hepatitis ical autoimmune or lupoid hepatitis), autoimmune mediated hypoglycaemia,
autoimmune neutropaenia, autoimmune thrombocytopaenia, mune thyroid disease, B
cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, bronchiolitis
obliterans, bundle branch block, burns, cachexia, c arrhythmias, cardiac stun syndrome,
cardiac tumors, cardiomyopathy, pulmonary bypass inflammation se, cartilage
lant rejection, cerebellar cortical rations, cerebellar disorders, chaotic or
multifocal atrial tachycardia, chemotherapy associated disorders, chlamydia, choleosatatis,
chronic alcoholism, chronic active hepatitis, chronic e syndrome, chronic immune
disease associated with organ transplantation, chronic philic pneumonia, c
inflammatory pathologies, chronic mucocutaneous candidiasis, chronic obstructive pulmonary
disease (COPD), c salicylate intoxication, common varied immunodeficiency (common
variable hypogammaglobulinaemia), conjunctivitis, connective tissue disease associated
interstitial lung disease, contact dermatitis, Coombs ve haemolytic anaemia, cor
pulmonale, Creutzfeldt-Jakob disease, cryptogenic autoimmune hepatitis, cryptogenic
fibrosing alveolitis, culture negative sepsis, cystic fibrosis, cytokine y associated
disorders, Crohn's disease, dementia pugilistica, demyelinating diseases, dengue hemorrhagic
fever, dermatitis, scleroderma, dermatologic conditions, dermatomyositis/polymyositis
associated lung disease, diabetes, diabetic arteriosclerotic disease, diabetes mellitus, e
Lewy body disease, dilated cardiomyopathy, d congestive cardiomyopathy, discoid
lupus erythematosus, disorders of the basal ganglia, disseminated intravascular ation,
Down's Syndrome in middle age, drug-induced interstitial lung disease, drug-induced
hepatitis, drug-induced movement disorders induced by drugs which block CNS dopamine,
receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy,
enteropathic synovitis, epiglottitis, Epstein-Barr virus infection, erythromelalgia,
extrapyramidal and llar disorders, familial hematophagocytic lymphohistiocytosis, fetal
thymus implant rejection, Friedreich's , functional peripheral arterial disorders, female
infertility, fibrosis, fibrotic lung disease, fungal sepsis, gas gangrene, gastric ulcer, giant cell
arteritis, glomerular nephritis, glomerulonephritides, Goodpasture's syndrome, goitrous
autoimmune hypothyroidism (Hashimoto's disease), gouty arthritis, graft ion of any
organ or tissue, graft versus host e, gram negative sepsis, gram positive sepsis,
granulomas due to intracellular organisms, group B streptococci (GBS) ion, Grave's
disease, haemosiderosis associated lung disease, hairy cell leukemia, hairy cell leukemia,
Hallerrorden-Spatz disease, Hashimoto's thyroiditis, hay fever, heart lant rejection,
hemachromatosis, hematopoietic malignancies (leukemia and lymphoma), tic anemia,
hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage, Henoch-
Schoenlein purpurea, Hepatitis A, Hepatitis B, Hepatitis C, HIV infection/HIV neuropathy,
Hodgkin's disease, hypoparathyroidism, Huntington's chorea, hyperkinetic nt
disorders, hypersensitivity reactions, hypersensitivity nitis, hyperthyroidism,
netic movement ers, hypothalamic-pituitary-adrenal axis evaluation, idiopathic
Addison's disease, idiopathic leucopaenia, idiopathic ary fibrosis, idiopathic
thrombocytopaenia, idiosyncratic liver disease, infantile spinal muscular atrophy, infectious
diseases, inflammation of the aorta, inflammatory bowel disease, insulin ent diabetes
mellitus, interstitial pneumonitis, iridocyclitis/uveitis/optic neuritis, ia-reperfusion
injury, ischemic stroke, le pernicious anaemia, le rheumatoid arthritis, le
spinal muscular atrophy, 's sarcoma, Kawasaki's disease, kidney transplant rejection,
legionella, leishmaniasis, leprosy, lesions of the corticospinal system, linear IgA disease,
ma, liver transplant rejection, Lyme disease, lymphederma, lymphocytic infiltrative lung
disease, malaria, male infertility idiopathic or NOS, malignant histiocytosis, malignant
melanoma, meningitis, meningococcemia, microscopic vasculitis of the kidneys, migraine
headache, mitochondrial multisystem disorder, mixed connective tissue e, mixed
connective tissue disease associated lung disease, monoclonal athy, multiple
myeloma, multiple systems degenerations (Mencel Dejerine-Thomas Shi-Drager and
Machado-Joseph), myalgic alitis/Royal Free Disease, enia gravis, microscopic
vasculitis of the kidneys, mycobacterium avium intracellulare, mycobacterium tuberculosis,
myelodyplastic syndrome, myocardial infarction, myocardial ischemic disorders,
nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, nephrotic
syndrome, neurodegenerative es, neurogenic I muscular atrophies, neutropenic fever,
Non-alcoholic Steatohepatitis, occlusion of the abdominal aorta and its branches, occlusive
arterial disorders, organ transplant ion, orchitis/epidydimitis, orchitis/vasectomy reversal
procedures, organomegaly, rthrosis, osteoporosis, ovarian failure, pancreas lant
rejection, parasitic diseases, parathyroid transplant rejection, Parkinson's disease, pelvic
inflammatory disease, pemphigus vulgaris, gus foliaceus, pemphigoid, perennial
rhinitis, pericardial disease, peripheral atherlosclerotic disease, peripheral vascular disorders,
peritonitis, ious , phacogenic uveitis, pneumocystis carinii pneumonia,
pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal
gammopathy, and skin changes syndrome), post perfusion syndrome, post pump syndrome,
post-MI cardiotomy syndrome, postinfectious interstitial lung disease, ure n
failure, primary biliary sis, primary sclerosing hepatitis, primary myxoedema, primary
pulmonary hypertension, primary sclerosing cholangitis, primary vasculitis, Progressive
supranucleo Palsy, psoriasis, psoriasis type 1, psoriasis type 2, psoriatic arthropathy,
pulmonary hypertension secondary to connective tissue disease, pulmonary manifestation of
polyarteritis nodosa, post-inflammatory interstitial lung disease, radiation fibrosis, radiation
therapy, Raynaud's phenomenon and disease, d's disease, Refsum's disease, regular
narrow QRS ardia, 's disease, renal disease NOS, renovascular hypertension,
reperfusion injury, restrictive cardiomyopathy, rheumatoid arthritis associated interstitial lung
disease, rheumatoid spondylitis, sarcoidosis, Schmidt's syndrome, scleroderma, senile chorea,
Senile Dementia of Lewy body type, sepsis syndrome, septic shock, seronegative
arthropathies, shock, sickle cell anemia, Sjögren's disease associated lung disease, Sjörgren's
syndrome, skin allograft rejection, skin changes syndrome, small bowel transplant rejection,
sperm autoimmunity, multiple sclerosis (all subtypes), spinal ataxia, spinocerebellar
degenerations, spondyloarthopathy, sporadic, polyglandular deficiency type I, sporadic
polyglandular deficiency type II, Still's disease, streptococcal myositis, stroke, structural
lesions of the cerebellum, Subacute sclerosing panencephalitis, sympathetic ophthalmia,
Syncope, syphilis of the cardiovascular , ic anaphylaxis, systemic matory
response syndrome, systemic onset juvenile rheumatoid arthritis, systemic lupus
erythematosus, systemic lupus erythematosus-associated lung disease, systemic sclerosis,
systemic sclerosis-associated interstitial lung disease, T-cell or FAB ALL, Takayasu's
disease/arteritis, Telangiectasia, Th2 Type and Th1 Type mediated es, thromboangitis
obliterans, ocytopenia, ditis, toxicity, toxic shock syndrome, transplants,
/hemorrhage, type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), type B
insulin resistance with osis nigricans, type III hypersensitivity reactions, type IV
hypersensitivity, ulcerative c arthropathy, ulcerative colitis, unstable , uremia,
urosepsis, urticaria, uveitis, valvular heart diseases, varicose veins, itis, vasculitic
diffuse lung disease, venous diseases, venous thrombosis, ventricular fibrillation, vitiligo
acute liver disease, viral and fungal infections, vital encephalitis/aseptic meningitis, vitalassociated
hemaphagocytic syndrome, Wegener's omatosis, Wernicke-Korsakoff
syndrome, Wilson's disease, xenograft rejection of any organ or tissue, yersinia and
salmonella-associated arthropathy and the like.
s and Experimentals
The following abbreviations have the meanings indicated. ADDP means
1,1'-(azodicarbonyl)dipiperidine; AD-mix-E means a mixture of (DHQD)2PHAL, K3Fe(CN)6,
K2CO3, and K2SO4; 9-BBN means 9-borabicyclo(3.3.1)nonane; Boc means
utoxycarbonyl; (DHQD)2PHAL means hydroquinidine 1,4-phthalazinediyl diethyl ether;
DBU means 1,8-diazabicyclo[5.4.0]undecene; DIBAL means diisobutylaluminum e;
DIEA means diisopropylethylamine; DMAP means N,N-dimethylaminopyridine; DMF
means N,N-dimethylformamide; dmpe means 1,2-bis(dimethylphosphino)ethane; DMSO
means dimethylsulfoxide; dppb means s(diphenylphosphino)-butane; dppe means 1,2-
bis(diphenylphosphino)ethane; dppf means 1,1'-bis(diphenylphosphino)ferrocene; dppm
means 1,1-bis(diphenylphosphino)methane; EDAC·HCl means 1-(3-dimethylaminopropyl)
ethylcarbodiimide hloride; Fmoc means fluorenylmethoxycarbonyl; HATU means
O-(7-azabenzotriazolyl)-N,N'N'N'-tetramethyluronium hexafluorophosphate; HMPA
means hexamethylphosphoramide; IPA means isopropyl alcohol; MP-BH3 means
macroporous triethylammonium methylpolystyrene cyanoborohydride; TEA means
ylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; NCS means
N-chlorosuccinimide; NMM means N-methylmorpholine; NMP means N-methylpyrrolidine;
PPh3 means triphenylphosphine.
The following schemes are presented to provide what is believed to be the most
useful and readily understood description of procedures and conceptual aspects of this
invention. Compounds of this invention may be made by tic chemical processes,
examples of which are shown . It is meant to be understood that the order of the steps
in the processes may be varied, that ts, solvents and reaction conditions may be
substituted for those specifically mentioned, and that vulnerable moieties may be protected
and deprotected, as necessary.
Schemes
Scheme 1
(R1)m (R2)n (R1)m (R2)n
N O +
X N O
O O (2) O
HN O
H (1) X (3)
X3 N Z1
(R1)m (R2)n
(R1)m (R2)n
(R3)p
(5) N N Z1
HN O (R3)p Br
HN O
(4) X (6)
(R1)m (R2)n
N N Z1
HN O (R3)p B
X (7) O
As shown in Scheme 1, nds of formula (1), n R1, R2, n, and m are as
described herein, can be reacted with compounds of formula (2) wherein X is as described
herein, in the presence of a carboxyl activating agent such as but not limited to N-(3-
dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride, and a st such but not
limited to 4-dimethylaminopyridine, to provide compounds of formula (3). The reaction is
typically performed at room temperature in a solvent such as but not limited to
dichloromethane. Compounds of formula (4) can be prepared by reacting nds of
formula (3) with an acid such as but not d to hydrochloric acid in a solvent such as but
not d to 1,4-dioxane. Compounds of formula (4) can be reacted with compounds of
a (5), wherein Z1, R3 and p are as described herein and X3 is chloro or fluoro, in the
presence of a base such as but not limited to cesium ate, to provide compounds of
formula (6). The reaction is typically performed at an elevated temperature in a solvent such
as but not limited to N,N-dimethylacetamide. Compounds of formula (7) can be prepared by
ng compounds of formula (6) with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane in
tetrahydrofuran, in the presence of a base such as but not limited to triethylamine, and a
catalyst such as but not limited to [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane. The on is
typically performed at elevated temperature and with the addition of a solvent such as but not
limited to acetonitrile. Additionally, the reaction may be performed in a microwave reactor.
Scheme 2
(R1)m (R2)n B (R1)m
HO Y1 L1 Y2 (R2)n
N N Z1
or N N Z1
HN O (R3)p Br M HN O Y1 L1 Y2
X Y1 L1 Y2 (R3)p
(6) X
(8a)
(R1)m (R2)n
(R1)m
X1 (R2)n
N N Z1 Y1 L1 Y2
(9) N N Z1
HN O (R3)p B
X (7) O HN O Y1 L1 Y2
(R3)p
(I)
After preparation as described in Scheme 1, compounds of a (6) can be reacted
with a boronic acid (or the boronate equivalent) of formula (8) or an organotin or organozinc
halide compound of formula (8a) wherein Y1, L1, and Y2 are as described herein, and M is
tributyltin or a zince halide, under Suzuki, Stille, or Negishi coupling conditions known to
those skilled in the art and y available in the ture to provide compounds of formula
(I). Alternatively, compounds of formula (7), which can be prepared from compounds of
formula (6) as described in Scheme 1, can be reacted with compounds of formula (9) wherein
X1 is a triflate or halide, and Y1, L1, and Y2 are as bed herein, under Suzuki coupling
conditions known to those skilled in the art and readily available in the literature to provide
compounds of formula (I).
Scheme 3
Rx1 Rx1
L1 Y2 Rx1
Rx2-X2
N (11) (13) N
NH Rx2 N
(10) (12) L1 Y2
L1 Y2 (14)
Rx2 N (7)
L1 Y2
(15)
(R1)m (R2)n
N N Z1
HN O
(R3)p N
X N
O (6) (17) L1 Y2
Rx2 N
L1 Y2
(18)
As shown in Scheme 3, pyrazoles of formula (10), wherein Rx1 is hydrogen or a
substituent on Y1 as described herein, can be reacted with alcohols of formula (11), wherein
L1 and Y2 are as bed herein, and cyanomethylenetributylphosphorane, to provide
nds of formula (12). The reaction is lly med at ambient temperature in a
solvent such as but not limited to toluene. Compounds of formula (14) can be prepared by
adding compounds of formula (13) wherein Rx2 is an appropriate substituent as described
herein for substituents on Y1, and X2 is a halide, to a cold solution of compounds of formula
(12) treated with n-butyllithium in hexanes. The reaction is typically performed in a solvent
such as but not limited to tetrahydrofuran. Compounds of a (14) can be treated with N-
bromosuccinimide or N-iodosuccinimideto provide compounds of formula (15), wherein X4
is bromo or iodo. The reaction is typically performed in a solvent such as N,N-
dimethylformamide. Compounds of formula (15) can be reacted with nds of formula
(7) under Suzuki ng conditions known to those skilled in the art and readily available in
the literature to provide nds of formula (17), which are representative of compounds
of formula (I). Alternatively, compounds of formula (15) can be reacted with triisopropyl
borate, in the presence of n-butyllithium in s, followed by pinacol to provide
nds of formula (18). The additions are typically performed at low temperature in a
solvent such as but not limited to tetrahydrofuran, toluene, or mixtures thereof. Alternatively,
compounds of the a (15) can be treated with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane in
the presence of a palladium catalyst system such as but not limited to
bis(acetonitri1e)palladium ride and SPhos in a solvent such as but not limited to 1.4-
dioxane to provide compounds of the formula 18. The reaction is typically performed at
elevated temperature. Compounds of formula (18) can be reacted with compounds of formula
(6) under Suzuki coupling conditions known to those skilled in the art and y available in
the literature to provide compounds of formula (17). which are representative of compounds
of formula (I).
Scheme4
R"1 O‘L -v1_ 2 Rx1 R"1
x3 y? R“ R (11)
Rx3 | \ RB 0—8
(N) R’Q NU I \
21NL1-”(22) Rx3
y2 - Y2 RX2 N
(23) UY2
(24)
a\ %)
(R‘)m (R6,.
\ 11 N z1
\E \ Rx1
H'.‘ 0 <th%R”
Rx2 N\
(25) L‘~v2
Pyrroles of formula (21) wherein R’“. R”. and R"3 are hydrogen or are as described
herein for substituents on Y1, can be reacted with alcohols of formula (1 1). wherein Y2 and L1
are as described herein, and cyanomethylenetributylphosphorane. to provide nds of
formula (22). The reaction is typically performed at ambient temperature in a solvent such as
but not limited to toluene. Compounds of formula (22) can be treated with N-
bromosuccinimide to provide compounds of formula (23). The reaction is typically
performed in a solvent such as N.N-dimethylformamide. Compounds of formula (23) can be
reacted with triisopropyl borate. in the ce of n-butyllithium in s. followed by
pinacol to e compounds of fonnula (24). The additions are typically performed at low
temperature in a solvent such as but not limited to tetrahydrofuran, toluene, or mixtures
thereof. Alternatively. nds of the formula (23) can be treated with 4.4.5.5-
tetramethyl-l,3,2-dioxaborolane in the presence of a palladirun st system such as but not
limited to bis(acetonitrile)palladium dichloride and SPhos in a solvent such as but not limited
to 1.4—dioxane to e compounds of the formula (24). The reaction is typically performed
at an elevated temperature. Compounds of formula (24) can be reacted with compounds of
formula (6) under Suzuki ng conditions known to those skilled in the art and y
available in the literature to e compounds of formula (25). which are representative of
~143—
compounds of formula (I). Alternatively, compounds of formula (23) can be reacted with
nds of a (7) under Suzuki coupling conditions known to those skilled in the art
and readily available in the literature to provide nds of formula (25), which are
entative of compounds of formula (I).
Scheme 5
OH Y1
CO2Rx4 CO2Rx4 Y1-H
RX2X1 Rx2 Rx2
(23A) (24A) Rx2
Z Z Z Z
n n n n
Rx1 Rx1 Rx1 Rx1
(24B) (25A)
(22A) (23B)
Compounds of formula (22A), wherein Z is O, a substituted or unsubstituted N, or a
substituted or unsubstituted C; Rx1 is hydrogen or is as bed herein for substituents on
Y2; Rx4 is alkyl; and n is 0, 1, or 2; can be added to a cooled solution of lithium
diisopropylamide, followed by the addition of compounds of formula (23A); wherein Rx2 is
an appropriate substituent as described herein for substituents on Y1, and X1 is a halide; to
provide compounds of formula (23B). The reaction is typically performed at low temperature
before warming to ambient temperature in a solvent such as but not limited to
tetrahydrofuran. Compounds of formula (23B) can be reacted with LiAlH4 to provide
compounds of formula (24B). The reaction is typically performed at an elevated temperature
in a solvent such as but not limited to diethyl ether. Compounds of formula (25A) can be
ed by reacting compounds of formula (24B) with compounds of formula (24A) wherein
Y1 is as described herein; and cyanomethylenetributylphosphorane. The reaction is typically
performed at ambient temperature in a solvent such as but not d to toluene. nds
of formula (25A) can be processed in a manner similar to nds of formula (12) in
Scheme 3 and compounds of formula (22) in Scheme 4 to provide nds of formula (I).
Scheme 6
Y1 Y1
O Y1-H
O OH Rx2-X2 O Rx2
(24A)
(13)
Rx1 n Rx1 n Rx1 n Rx1 n
(26) (27) (28) (29)
As shown in Scheme 6, compounds of formula (27), wherein Rx1 is hydrogen or a
substituent on Y1 as described herein, can be prepared by reacting compounds of a (26)
with trimethylsulfonium iodide, in the presence of potassium tert-butoxide. The reaction is
typically performed at t temperature in an anhydrous solvent such as but not limited to
dimethylsulfoxide. Compounds of formula (27) can be added to a mixture of compounds of
formula (24A) and a base such as but not limited to cesium ate, to provide compounds
of formula (28). The reaction is typically performed at elevated temperature in a t such
as but not limited to N,N-dimethylformamide, and may be performed in a microwave r.
Compounds of formula (28) can be treated with sodium hydride, followed by the addition of
compounds of formula (13) to provide compounds of formula (29). The reaction is typically
performed at ambient temperature in a solvent such as but not limited to tetrahydrofuran, and
may involve the use of hexamethylphosphoramide. Compounds of formula (29) can be
processed in a manner similar to compounds of a (12) in Scheme 3 and compounds of
formula (22) in Scheme 4 to provide compounds of formula (I).
Scheme 7
(R1)m (R2)n
MY1 L1 Y2 (R1)m (R2)n
X3 N Z1 X3 N Z1 HN O
(33) X (4)
N N Z1
Br Y1 L1 Y2
(R3)p (R3)p
(34) HN O Y1 L1 Y2
(32) (R3)p
(I)
Compounds of formula (33) wherein M is a c acid, boronate, or tributlytin
attached to Y1 and Y1, L1, and Y2 are as described herein, and X3 is chloro or fluoro; can be
reacted with compounds of formula (32) wherein Z1, R3, and p are as bed herein, under
Suzuki or Stille coupling conditions known to those skilled in the art and readily available in
the literature to provide compounds of formula (34). Compounds of formula (34) can be
d with compounds of formula (4), in the presence of a base such as but not limited to
cesium carbonate, to provide compounds of formula (I). The reaction is lly performed
at an elevated ature in a solvent such as but not limited to N,N-dimethylacetamide.
Scheme 8
SnBu3
F N Z1
F N Z1
Bu3Sn Br
(36A) N (37) N
N3 L1-Y2 N N
Rx2 N N
(35) Rx2
L1 Y2 L1 Y2
(36) (38)
(R1)m (R2)n
(R1)m
NH (R2)n
HN O N N Z1
HN O N
Rx2 N
(39)
L1 Y2
Triazoles of formula (36) can be prepared by reacting azides of formula (35), wherein
L1 and Y2 are as described herein, with compounds of formula (36A) wherein Rx2 is alkyl,
under ions known to those skilled in the art and readily available in the literature.
Compounds of formula (37), wherein Z1 is as described herein, can be d with
nds of formula (36) under Stille coupling conditions known to those skilled in the art
and readily available in the literature to e compounds of formula (38). Compounds of
formula (4), wherein R1, R2, X, m and n are as bed herein, can be reacted with
compounds of a (38), in the presence of a base such as but not limited to cesium
carbonate, to provide compounds of formula (39), which are representative of compounds of
formula (I). The reaction is typically performed at an elevated temperature in a solvent such
as but not limited to N,N-dimethylacetamide.
The following examples are presented to provide what is believed to be the most
useful and readily understood description of procedures and conceptual aspects of this
invention. The exemplified compounds were named using ACD/ChemSketch Version 5.06
(05 June 2001, ed Chemistry pment Inc., Toronto, Ontario), ACD/ChemSketch
Version 12.01 (13 May 2009), Advanced Chemistry Development Inc., Toronto, Ontario), or
ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, MA). ediates were named using
ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, MA).
EXAMPLE 1
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H-
pyrazolyl)pyridinecarboxylic acid
EXAMPLE 1A
tert-butyl 8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
To a solution of t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolinecarboxylic
acid (6.8 g) and benzo[d]thiazolamine (5.52 g) in dichloromethane (80 mL) was added 1-
ethyl[3-(dimethylamino)propyl]-carbodiimide hydrochloride (9.4 g) and 4-
dimethylaminopyridine (6 g). The mixture was stirred at room temperature overnight. The
reaction mixture was d with dichloromethane (400 mL), washed with 5% aqueous HCl,
water, and brine, and dried over Na2SO4. The mixture was filtered and the filtrate was
concentrated under reduced pressure to provide the title compound.
EXAMPLE 1B
N-(benzo[d]thiazolyl)-1,2,3,4-tetrahydroisoquinolinecarboxamide dihydrochloride
To a solution of EXAMPLE 1A (8.5 g) in dichloromethane (80 mL) was added 2N
HCl in ether (80 mL). The reaction mixture was stirred at room temperature overnight and
concentrated under reduced pressure to provide the title compound.
E 1C
tert-butyl 3-bromochloropicolinate
Tosyl chloride (7.7 g) was added to a solution of robromo picolinic acid (4
g) and pyridine (9.2 mL) in t-butanol (33 mL) at 0°C. The reaction was then d at room
ature for 12 hours. NaHCO3 (aqueous, ted) was then added and the mixture was
extracted three times with ethyl acetate. The combined organic phases were washed with
brine and dried over Na2SO4. Filration and evaporation of the organic solvent provided the
title compound which was used in the next step without further purification.
EXAMPLE 1D
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)
bromopicolinate
EXAMPLE 1C (0.736 g), EXAMPLE 1B (1.62 g), and Cs2CO3 (4.1 g) were stirred in
12 mL of anhydrous N,N-dimethylacetamide at 120°C for 12 hours. The cooled reaction
mixture was then diluted with ethyl acetate and 10% citric acid. The c phase was
washed three times with citric acid, once with water and brine, and dried over Na2SO4.
tion and concentration afforded crude material, which was chromatographed on silica
gel using 0-40% ethyl acetate in hexanes to provide the title compound.
EXAMPLE 1E
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)
(1-benzyl-1H-pyrazolyl)picolinate
A mixture of EXAMPLE 1D (0.113 g), 1-benzyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole (0.063 g), tetrakis(triphenylphosphine)palladium(0) (0.023 g)
and CsF (0.091 g) in methoxyethane (2 mL) and methanol (1 mL) was heated at 120oC
for 30 minutes under microwave heating conditions. The reaction mixture was ioned
n water and ethyl e. The aqueous layer was extracted with additional ethyl
acetate twice. The combined organic layers were washed with brine, dried over MgSO4,
filtered, and trated. The residue was purified by flash column chromatography on
silica gel eluting with 35% ethyl acetate in hexanes to afford the title nd.
EXAMPLE 1F 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]
(1-benzyl-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 1E (100 mg) in dichloromethane (3 mL) was treated with trifluoroacetic
acid (3 mL). The reaction mixture was stirred at room temperature for 4 hours. The volatiles
were removed under reduced pressure. The residue was purified by Prep HPLC using Gilson
system eluting with 20-80% itrile in water containing 0.1% v/v trifluoroacetic acid.
The desired ons were combined and -dried to provide the title compound. 1H
NMR (500 MHz, dimethylsulfoxide-d6) G ppm 12.86 (s, 1H), 8.04 (d, 1H), 7.92 (s, 1H), 7.80
(s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.61 (d, 1H), 7.67 (s, 1H), 7.42-7.50 (m, 2H), 7.23-7.38
(m, 7H), 6.94 (d, 1H), 5.33 (s, 2H), 4.94 (s, 2H), 3.86 (t, 2H), 3.00 (t, 2H).
EXAMPLE 2
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(pyridin
ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 2A
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
(pyridinylmethyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting 4-((4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazolyl)methyl)pyridine for 1-benzyl(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 2B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(pyridin
ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 2A for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (500 MHz, dimethylsulfoxide-d6) G ppm 12.87 (s, 1H), 8.70 (d,
2H), 8.04 (d, 1H), 8.02 (s, 1H), 7.80 (d, 1H), 7.73 (d, 1H), 7.67 (s, 1H), 7.62 (d, 1H), 7.34-
7.50 (m, 6H), 6.97 (d, 1H), 5.59 (s, 2H), 4.96 (s, 2H), 3.87 (t, 2H), 3.01 (t, 2H).
EXAMPLE 3
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(pyridin
ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 3A
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
(pyridinylmethyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting 3-((4-(4,4,5,5-tetramethyl-1,3,2-
orolanyl)-1H-pyrazolyl)methyl)pyridine for 1-benzyl(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 3B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(pyridin
ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 3A for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (s, 1H), 8.70 (d,
2H), 8.62-8.63 (m, 2H), 8.04 (d, 1H), 8.00 (s, 1H), 7.90 (d, 1H), 7.80 (d, 1H), 7.71 (d, 1H),
7.85-7.62 (m, 3H), 7.34-7.50 (m, 5H), 6.95 (d, 1H), 5.46 (s, 2H), 4.95 (s, 2H), 3.87 (t, 2H),
3.00 (t, 2H).
EXAMPLE 4
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-
ybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
E 4A
1-(benzyloxy)(bromomethyl)benzene
A e of nzyloxy)phenyl)methanol (2.14 g) and lithium bromide (1.0 g) in
N,N-dimethylformamide (20 mL) was cooled to 0ºC. To this solution was added PBr3 (1.0
mL). The solution was stirred at room temperature for 2 hours. The reaction e was
partitioned between water and ethyl acetate. The aqueous layer was extracted with additional
ethyl acetate, twice. The combined c layers were washed with brine, dried over
MgSO4, filtered, and concentrated. The residue was purified by flash column
chromatography on silica gel eluting with 5% ethyl acetate in hexanes to provide the title
compound.
EXAMPLE 4B
1-(4-(benzyloxy)benzyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
A mixture of EXAMPLE 4A (0.54 g) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-1H-pyrazole (0.377 g) in N,N-dimethylformamide (5 mL) was cooled to 0 ºC. To this
solution was added 60% sodium hydride (0.096 g). The solution was stirred at room
temperature overnight. The reaction mixture was ioned between water and ethyl acetate.
The aqueous layer was extracted with additional ethyl acetate twice. The combined organic
layers were washed with brine, dried over MgSO4, filtered, and concentrated. The e was
purified by flash column chromatography on silica gel eluting with 25% ethyl acetate in
hexanes to provide the title compound.
EXAMPLE 4C
utyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(4-
(benzyloxy)benzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE of 4B for 3-((4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazolyl)methyl)pyridine in EXAMPLE 1E.
EXAMPLE 4D
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(4-
hydroxybenzyl)-1H-pyrazolyl)picolinate
A mixture of EXAMPLE 4C (0 05 g) and 5% palladium on carbon (0.1 g) in ethanol
(5 mL) was treated with a balloon of hydrogen. The reaction mixture was stirred overnight.
The solid was removed by filtration, and filtrate was concentrated to provide the title
compound.
EXAMPLE 4E
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-
hydroxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 4D for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (500 MHz, ylsulfoxide-d 6) G ppm 12.84 (s, 1H), 8.04 (d,
1H), 7.83 (s, 1H), 7.79 (d, 1H), 7.69 (d, 1H), 7.61 (d, 1H), 7.54 (s, 1H), .50 (m, 1H),
7.42-7.46 (m, 1H), 7.34-7.38 (m, 2H), 7.08-7.12 (m, 2H), 6.93 (d, 1H), 6.69-6.73 (m, 2H),
5.17 (s, 2H), 4.94 (s, 2H), 3.86 (t, 2H), 2.99 (t, 2H).
EXAMPLE 5
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(1-
phenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 5A
The title compound was prepared by substituting (1-bromoethyl)benzene for
E 4A in EXAMPLE 4B.
E 5B
tert-butyl benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(1-
phenylethyl)-1H-pyrazolyl)picolinate
The title compound was ed by substituting EXAMPLE 5A for 3-((4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazolyl)methyl)pyridine in EXAMPLE 1E.
EXAMPLE 5C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(1-
phenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 5B for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.79 (s, 1H), 7.97 (d,
1H), 7.88 (s, 1H), 7.73 (d, 1H), 7.65 (d, 1H), 7.54 (d, 1H), 7.50 (s, 1H), 7.55-7.56 (m, 1H),
7.24-7.30 (m, 4H), 7.17-7.20 (m, 3H), 6.97 (d, 1H), 5.54 (q, 1H), 4.87 (s, 2H), 3.79 (t, 2H),
2.93 (t, 2H).
EXAMPLE 6
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{4-[2-
(dimethylamino)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 6A
tert-butyl 6-(8-(benzo[d]thiazolyl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)(1-(4-(benzyloxy)benzyl)-1H-pyrazolyl)picolinate
A e of E 4C (0.30 g) and (2-(chloromethoxy)ethyl)trimethylsilane
(0.094 g) in tetrahydrofuran (4 mL) was treated with triethylamine (0.122 g) at room
temperature. The reaction was stirred for 1 hour. The reaction mixture was partitioned
between water and ethyl e. The aqueous layer was extracted with additional ethyl
e twice. The combined organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated. The residue was purified by flash column chromatography on
silica gel eluting with 5% ethyl acetate in hexanes to e the title compound.
EXAMPLE 6B
tert-butyl 6-(8-(benzo[d]thiazolyl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)(1-(4-hydroxybenzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 6A for EXAMPLE 4C
in EXAMPLE 4D.
EXAMPLE 6C
tert-butyl 6-(8-(benzo[d]thiazolyl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)(1-(4-(2-(dimethylamino)ethoxy)benzyl)-1H-pyrazol
yl)picolinate
A mixture of EXAMPLE 6B (0.18 g), 2-(dimethylamino)ethanol (0.102 g), and
triphenylphosphine (0.299 g) in tetrahydrofuran (3 mL) was stirred for 5 minutes at 0 ºC. To
this solution was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (0.263 g). The on
mixture was stirred at room temperature for 16 hours. The solvent was d, and the
residue was purified by flash column chromatography on silica gel using 5-50% ethyl acetate
in hexanes to provide the title compound.
EXAMPLE 6D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{4-[2-
(dimethylamino)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid
E 6C (0.08 g) in dichloromethane (3 mL) was treated with trifluoroacetic
acid (3 mL). The reaction mixture was stirred at room temperature for 16 hours. The
volatiles were removed under reduced pressure. The residue was purified by Prep HPLC
using a Gilson system g with 20-80% acetonitrile in 0.1% water. The desired fractions
were ed and freeze-dried to provide the title compound. 1H NMR (500 MHz,
dimethylsulfoxide-d6) G ppm 9.55 (s, 1H), 8.03 (d, 1H), 7.88 (s, 1H), 7.78 (d, 1H), 7.68 (d,
1H), 7.60 (d, 1H), 7.54 (s, 1H), 7.41-7.48 (m, 2H), 7.33-7.36 (m, 2H), 7.25(d, 2H), 6.96 (d,
2H), 6.93 (d, Hz, 1H), 5.24 (s, 2H), 4.94 (s, 2H), 4.93 (s, 2H), 4.26-4.28 (m, 2H), 3.85 (t, 2H),
2.97-2.99 (m, 2H), 2.83 (s, 6H).
EXAMPLE 7
3-(1-benzyl-1H-pyrazolyl){8-[(5,6-difluoro-1,3-benzothiazolyl)carbamoyl]-3,4-
dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid
EXAMPLE 7A
methyl 2-(5-bromo(tert-butoxycarbonyl)pyridinyl)-1,2,3,4-
tetrahydroisoquinolinecarboxylate
A solution of methyl 1,2,3,4-tetrahydroisoquinolinecarboxylate (1.00 g),
EXAMPLE 1C (1.68 g) and cesium carbonate (2.56 g) was stirred together in N,N-
dimethylacetamide (10 mL) at 110°C overnight. The reaction was cooled, diluted with ethyl
acetate (50 mL) and washed with water (2 x 25 mL) and brine (25 mL), dried over
magnesium sulfate, filtered, and concentrated. Silica gel chromatography using 1-30% ethyl
acetate in hexanes provided the title compound.
EXAMPLE 7B
methyl 1-benzyl-1H-pyrazolyl)(tert-butoxycarbonyl)pyridinyl)-1,2,3,4-
tetrahydroisoquinolinecarboxylate
The title compound was prepared by substituting E 7A for EXAMPLE 1D
in E 1E.
EXAMPLE 7C
1-benzyl-1H-pyrazolyl)(tert-butoxycarbonyl)pyridinyl)-1,2,3,4-
tetrahydroisoquinolinecarboxylic
To a solution of EXAMPLE 7B (0.565 g) in tetrahydrofuran (4 mL) and methanol (2
mL) was added NaOH (1.292 ml, 1 M) and the reaction was stirred at room temperature
overnight. The reaction was diluted with ethyl acetate (50 mL) and quenched with 1N
aqueous HCl (1.3 mL) and diluted with water (20 mL). The organic layer was separated,
dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting
with a gradient of 0.5% to 3% methanol/dichloromethane provided the title compound.
EXAMPLE 7D
tert-butyl enzyl-1H-pyrazolyl)(8-(5,6-difluorobenzo[d]thiazolylcarbamoyl)-
3,4-dihydroisoquinolin-2(1H)-yl)picolinate
EXAMPLE 7C (0.086 g), 5,6-difluorobenzo[d]thiazolamine ( 0.034 g), 1-ethyl
[3-(dimethylamino)propyl]-carbodiimide hloride (0.048 g) and 4-
dimethylaminopyridine (0.041 g) were combined together in dichloromethane (1 mL) and
stirred overnight. The reaction was loaded onto silica gel and eluted using a gradient of
0.25% to 2.0% methanol/dichloromethane to provide the title compound.
EXAMPLE 7E
3-(1-benzyl-1H-pyrazolyl){8-[(5,6-difluoro-1,3-benzothiazolyl)carbamoyl]-3,4-
dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid
To a solution of EXAMPLE 7D (0.085 g) in dichloromethane (0.5 mL) was added
TFA (0.5 mL) and the reaction was d overnight. The reaction mixture was concentrated
and dried to provide the title compound. 1H NMR (300 MHz, ylsulfoxide-d 6) δ ppm
12.98 (s, 1H), 8.20 (dd, 1H), 7.93 -7.83 (m, 2H), 7.70 (d, 1H), 7.58 (dd, 2H), 7.47 -7.19 (m,
7H), 6.94 (d, 1H), 5.32 (s, 2H), 4.93 (s, 2H), 3.86 (t, 2H), 2.99 (t, 2H).
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(4-
fluorophenyl)ethyl]-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 8A
1-(4-fluorophenethyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was ed by substituting 1-(2-bromoethyl)fluorobenzene
for EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 8B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(4-
fluorophenethyl)-1H-pyrazolyl)picolinate
The title nd was prepared by substituting EXAMPLE 8A for 1-benzyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 8C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(4-
fluorophenyl)ethyl]-1H-pyrazolyl}pyridinecarboxylic acid
To EXAMPLE 8B (0.040 g) in dichloromethane (1 mL) was added TFA (1 mL) and
the reaction stirred overnight. The reaction was concentrated, dissolved in dichloromethane
and loaded onto silica gel and eluted using a gradient of 0.5% to 5%
methanol/dichloromethane to e the title compound. 1H NMR (300 MHz,
ylsulfoxide-d6) δ 13.04 (s, 1H), 12.84 (s, 1H), 8.04 (dd, 1H), 7.79 (d, 1H), 7.71 (d, 1H),
7.62 (t, 2H), 7.54 -7.32 (m, 5H), 7.22 -7.14 (m, 2H), 7.11 -7.01 (m, 2H), 6.93 (d, 1H), 4.94
(s, 2H), 4.30 (t, 2H), 3.86 (t, 2H), 3.08 (t, 2H), 3.00 (t, 2H).
EXAMPLE 9
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
chlorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 9A
tert-butyl 6-(8-(benzo[d]thiazolyl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)bromopicolinate
The title compound was prepared by substituting E 1D for EXAMPLE 4C
in EXAMPLE 6A.
EXAMPLE 9B
tert-butyl 6-(8-(benzo[d]thiazolyl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)(1H-pyrazolyl)picolinate
The title compound was prepared by substituting 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole for 1-benzyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-
1H-pyrazole and EXAMPLE 9A for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 9C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
chlorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
A on of EXAMPLE 9B (0.178 g), 1-(bromomethyl)chlorobenzene (0.080 g)
and cesium carbonate (0.170 g) was d together in N,N-dimethylformamide (2 mL) at
room temperature. After 3 hours, the reaction was diluted with ethyl acetate (25 mL) and
washed with water (20 mL), brine (20 mL), dried over magnesium sulfate, filtered, and
concentrated. The residue was dissolved in dichloromethane (1 mL) and treated with TFA (1
mL) and stirred overnight. The mixture was concentrated, dissolved in romethane and
loaded onto silica gel and eluted using a gradient of 0.5% to 4% methanol/dichloromethane to
provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.84 (s, 1H),
8.04 (dd, 1H), 7.95 (d, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.60 (dd, 2H), 7.53 -7.28 (m, 7H),
7.22-7.16 (m, 1H), 6.95 (d, 1H), 5.35 (s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).
EXAMPLE 10
3-(1-benzyl-1H-pyrazolyl){8-[(6-fluoro-1,3-benzothiazolyl)carbamoyl]-3,4-
dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid
EXAMPLE 10A
tert-butyl 3-(1-benzyl-1H-pyrazolyl)(8-(6-fluorobenzo[d]thiazolylcarbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)picolinate
The title compound was prepared according to the procedure in EXAMPLE 7D by
substituting 5,6-difluorobenzo[d]thiazolamine with 6-fluorobenzo[d}thiazolamine.
EXAMPLE 10B
enzyl-1H-pyrazolyl){8-[(6-fluoro-1,3-benzothiazolyl)carbamoyl]-3,4-
dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid
The title compound was prepared according to the procedure in EXAMPLE 7E by
substituting EXAMPLE 7D with EXAMPLE 10A. 1H NMR (300 MHz, ylsulfoxided6
) G ppm 12.87 (s, 1H), 7.95 (dd, 1H), 7.91 (s, 1H), 7.80 (dd, 1H), 7.70 (d, 1H), 7.59 (m,
2H), 7.32 (m, 9H), 6.94 (d, 1H), 5.32 (s, 2H), 4.93 (s, 2H), 3.86 (t, 2H), 3.00 (t, 2H).
EXAMPLE 11
3-(1-benzyl-1H-pyrazolyl){8-[(6-methoxy-1,3-benzothiazolyl)carbamoyl]-3,4-
dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid
EXAMPLE 11A
tert-butyl 3-(1-benzyl-1H-pyrazolyl)(8-(6-methoxybenzo[d]thiazolylcarbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)picolinate
The title compound was prepared according to the procedure in EXAMPLE 7D by
substituting 5,6-difluorobenzo[d]thiazolamine with 6-methoxybenzo[d]thiazolamine.
EXAMPLE 11B
enzyl-1H-pyrazolyl){8-[(6-methoxy-1,3-benzothiazolyl)carbamoyl]-3,4-
dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid
The title compound was prepared according to the procedure in EXAMPLE 7E by
substituting EXAMPLE 7D with EXAMPLE 11A. 1HNMR (300 MHz, dimethylsulfoxided6
) G ppm 12.72 (s, 1H), 7.92 (s, 1H), 7.70 (dd, 2H), 7.62 (d, 1H), 7.58 (m, 2H), 7.32 (m, 8H),
7.07 (dd, 1H), 6.94 (d, 1H), 5.32 (s, 2H), 4.93 (s, 2H), 3.85 (m, 5 H), 2.99 (t, 2H).
EXAMPLE 12
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-3,5-
dimethyl-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 12A
yl-3,5-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 3,5-dimethyl(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)-1H-pyrazole for ,5,5-tetramethyl-1,3,2-dioxaborolanyl)-
1H-pyrazole and benzyl bromide for EXAMPLE 4A in E 4B.
EXAMPLE 12B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
benzyl-3,5-dimethyl-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 12A for 1-benzyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
E 12C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-3,5-
dimethyl-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 12B for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (500 MHz, dimethylsulfoxide-d6) G ppm 12.86 (s, 1H), 8.04 (d,
1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.44-7.49 (m, 3H), 7.31-7.39 (m, 4H), 7.27 (d, 1H), 7.10 (d,
2H), 6.96 (d, 1H), 5.23 (s, 1H), 4.97 (s, 2H), 3.90 (t, 2H), 3.02 (t, 2H), 1.97 (s, 3H), 1.95 (s,
3H).
EXAMPLE 13
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
methylbenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 13A
ethylbenzyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 3-methylbenzyl bromide for
EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 13B
utyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(3-
methylbenzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 13A for yl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 13C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
methylbenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 13B for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 1H), 8.04 (d,
1H), 7.90 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 760-7.83 (m, 3H), 7.56 (s, 1H), 7.34-7.50 (m,
5H), 7.22(t, 1H), .10 (m, 3H), 6.94 (d, 1H), 5.27 (s, 1H), 4.94(s, 2H), 3.86 (t, 2H), 3.00
(t, 2H), 2.27 (s, 3H).
EXAMPLE 14
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
methoxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 14A
1-(3-methoxybenzyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 3-methoxylbenzyl bromide for
EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 14B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(3-
methoxybenzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 14A for 1-benzyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in E 1E.
EXAMPLE 14C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
methoxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 14B for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (s, 1H), 8.04 (d,
1H), 7.91 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 761 (d, 1H), 7.57 (s, 1H), 7.52-7.50 (m, 2H),
7.34-7.38 (m, 2H), .27 (m, 1H), 6.94 (d, 1H), 6.84-6.86 (m, 1H), 6.79-6.80 (m, 2H),
5.29 (s, 2H), 4.94(s, 2H), 3.88 (t, 2H), 3.71 (s, 3H), 3.00 (t, 2H).
EXAMPLE 15
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-
chlorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 15A
1-(4-chlorobenzyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title nd was prepared by substituting 1-(bromomethyl)chlorobenzene
for E 4A in EXAMPLE 4B.
EXAMPLE 15B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-
chlorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
A solution of EXAMPLE 1D (0.205 g), EXAMPLE 15A (0.165 g), cesium fluoride
(0.197 g) and tetrakis(triphenylphosphine)palladium(0) (0.030 g) were stirred together in 1,2-
dimethoxyethane (1 mL) and methanol (0.5 mL) and heated in a e Initiator microwave
reactor at 120°C for 30 minutes. The reaction was trated, loaded onto silica gel and
eluted using a gradient of 0.5% to 2.5% methanol/dichloromethane to give the corresponding
ester which was dissolved in dichloromethane (1 mL) and treated with TFA (1 mL). After
stirring overnight the reaction was concentrated, loaded onto silica gel and eluted using a
gradient of 0.5% to 2.5% methanol/dichloromethane to provide the title nd. 1H NMR
(300 MHz, dimethylsulfoxide-d6) δ ppm 12.85 (s, 2H), 8.04 (dd, 1H), 7.92 (d, 1H), 7.79 (d,
1H), 7.70 (d, 1H), 7.61 (d, 1H), 7.58 (d, 1H), 7.52 -7.31 (m, 6H), 7.29 -7.22 (m, 2H), 6.94
(d, 1H), 5.33 (s, 2H), 4.94 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).
EXAMPLE 16
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(benzyloxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 16A
zyloxy)(bromomethyl)benzene
The title compound was prepared by substituting (3-(benzyloxy)phenyl)methanol for
(4-(benzyloxy)phenyl)methanol in E 4A.
EXAMPLE 16B
1-(3-(benzyloxy)benzyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 16A for EXAMPLE 4A
in EXAMPLE 4B.
EXAMPLE 16C
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(3-
(benzyloxy)benzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 16B for yl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 16D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(benzyloxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 16C for E 1E
in EXAMPLE 1F. 1H NMR (500 MHz, ylsulfoxide-d 6) G ppm 12.86 (s, 1H), 8.04 (d,
1H), 7.91 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 761 (d, 1H), 7.57 (s, 1H), 7.32-7.51 (m, 9H),
7.06 (d, 2H), 6.92-6.96 (m, 2H), 6.80 (d, 1H), 6.84-6.86 (m, 1H), 6.79-6.80 (m, 2H), 5.29 (s,
2H), 5.07 (s, 2H), .4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).
EXAMPLE 17
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
ybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 16D for EXAMPLE 4C
in EXAMPLE 4D. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (s, 1H), 9.41 (s,
1H), 8.04 (d, 1H), 7.89 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 761 (d, 1H), 7.57 (s, 1H), 7.42-7.50
(m, 2H), 7.34-7.38 (m, 2H), 7.11 (t, 1H), 6.94 (d, 1H), 6.62-6.67 (m, 2H), 5.23 (s, 2H), 4.94
(s, 2H), 3.86 (t, 2H), 3.00 (t, 2H).
EXAMPLE 18
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{3-[2-
(dimethylamino)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 18A
tert-butyl 6-(8-(benzo[d]thiazolyl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)(1-(3-(benzyloxy)benzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting E 16C for EXAMPLE 4C
in EXAMPLE 6A.
EXAMPLE 18B
tert-butyl 6-(8-(benzo[d]thiazolyl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)(1-(3-hydroxybenzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 18A for EXAMPLE 4C
in EXAMPLE 4D.
EXAMPLE 18C
utyl 6-(8-(benzo[d]thiazolyl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)(1-(3-(2-(dimethylamino)ethoxy)benzyl)-1H-pyrazol
yl)picolinate
The title compound was prepared by substituting EXAMPLE 18B for EXAMPLE 6B
in EXAMPLE 6C.
EXAMPLE 18D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{3-[2-
(dimethylamino)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 18C for EXAMPLE 6C
in EXAMPLE 6D. 1H NMR (500 MHz, dimethylsulfoxide-d6) G ppm 12.86 (s, 1H), 9.55 (s,
1H), 8.04 (d, 1H), 7.92 (s, 1H), 7.80 (d, 1H), 7.71 (d, 1H), 762 (d, 1H), 7.59 (s, 1H), 7.42-7.50
(m, 2H), 7.28-7.38 (m, 3H), 6.89-6.96 (m, 3H), 6.85 (s, 3H), 5.31 (s, 2H), 4.95 (s, 2H), 4.25-
4.28 (m, 2H), 3.87 (t, 2H), 3.00 (t, 2H), 2.84 (s, 6H).
EXAMPLE 19
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl
methyl-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 19A
1-benzylmethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was ed by tuting 3-methyl(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)-1H-pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-
1H-pyrazole and benzyl bromide for EXAMPLE 4A in EXAMPLE 4B.
E 19B
The title compound was prepared by substituting EXAMPLE 19A for 1-benzyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 19C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl
methyl-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 19B for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (s, 1H), 8.04 (d,
1H), 7.79 (d, 1H), 7.66 (s, 1H), 762 (d, 1H), 7.54 (d, 1H), 7.43-7.50 (m, 2H), 7.21-7.38 (m,
7H), 6.94 (d, 1H), 5.32 (s, 2H), 4.95 (s, 2H), 3.89 (t, 2H), 3.01 (t, 2H), 2.03 (s, 3H).
EXAMPLE 20
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl
methyl-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 20A
1-benzylmethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared as a minor regioisomer using the ure
described in E 19A.
EXAMPLE 20B
utyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
benzylmethyl-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 20A for 1-benzyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 20C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl
-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by tuting EXAMPLE 20B for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 1H), 8.04 (d,
1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.52 (d, 1H), 7.43-7.49 (m, 2H), 7.31-7.38 (m, 5H), 7.25-7.28
(m. 1H), 7.11 (d, 2H), 6.95 (d, 1H), 5.32 (s, 2H), 4.96(s, 2H), 3.88 (t, 2H), 3.01 (t, 2H), 2.08
(s, 3H).
EXAMPLE 21
3-(1-benzyl-1H-pyrazolyl){8-[(7-chloro-1,3-benzothiazolyl)carbamoyl]-3,4-
dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid
EXAMPLE 21A
tert-butyl 3-(1-benzyl-1H-pyrazolyl)(8-(7-chlorobenzo[d]thiazolylcarbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)picolinate
The title compound was prepared according to the procedure in EXAMPLE 7D by
substituting 5,6-difluorobenzo[d]thiazolamine with 4-chlorobenzo[d}thiazolamine.
EXAMPLE 21B
3-(1-benzyl-1H-pyrazolyl){8-[(7-chloro-1,3-benzothiazolyl)carbamoyl]-3,4-
dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid
The title compound was prepared according to the ure in EXAMPLE 7E by
substituting E 7D with EXAMPLE 21A. 1H NMR (300 MHz, dimethylsulfoxided6
) G ppm 13.07 (s, 1H), 7.91 (s, 1H), 7.79 (d, 1H), 7.71 (d, 2H), 7.63 (d, 1H), 7.57 (s, 1H),
7.37 (m, 8H), 6.96 (d, 2H), 5.32 (s, 2H), 4.94 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).
EXAMPLE 22
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[6-
(pyrrolidinyl)pyridinyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 22A
2-(pyrrolidinyl)((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazol
yl)methyl)pyridine
The title compound was prepared by substituting momethyl)(pyrrolidin
yl)pyridine for EXAMPLE 4A in E 4B.
EXAMPLE 22B
tert-butyl benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((6-
(pyrrolidinyl)pyridinyl)methyl)-1H-pyrazolyl)picolinate
EXAMPLE 1D (0.100 g), EXAMPLE 22A (0.094 g),
tetrakis(triphenylphosphine)palladium(0) (10.22 mg) and cesium carbonate (0.173 g) were
stirred together in N,N-dimethylformamide (0.6 mL), dioxane (0.4 mL), and water (0.2 mL)
and the reaction degassed with nitrogen and heated at 100°C for 1 hour. The reaction was
diluted with ethyl acetate (25 mL) and washed with water (25 mL) and brine (25 mL), dried
over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with
methanol/dichloromethane provided the title compound.
EXAMPLE 22C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[6-
(pyrrolidinyl)pyridinyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 22B for E 8B
in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.86 (s, 1H), 8.04 (d,
1H), 7.96 (d, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.65 – 7.32 (m, 7H), 6.95 (, 1H), 6.52 (d, 1H),
6.21 (d, 1H), 5.30 (s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.40 (tt, 4H), 3.00 (t, 2H), 1.94 (t, 4H).
EXAMPLE 23
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-phenyl-1H-
pyrazolyl)pyridinecarboxylic acid
EXAMPLE 23A
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
phenyl-1H-pyrazolyl)picolinate
The title nd was prepared by substituting 1-phenyl(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)-1H-pyrazole for 1-benzyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 23B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-phenyl-1H-
pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 23B for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.87 (s, 1H), 8.57 (s,
1H), 8.05 (d, 79-7.83 (m, 5H), 7.62 (d, 1H), 7.43-7.53 (m, 5H), 7.30-7.39 (m, 3H),
7.01 (d, 1H), 4.98 (s, 2H), 3.90 (t, 2H), 3.02 (t, 2H).
EXAMPLE 24
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
cyanobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
E 24A
3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazolyl)methyl)benzonitrile
The title compound was prepared by substituting 3-(bromomethyl)benzonitrile for
EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 24B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(3-
enzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 24A for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 24C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
cyanobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 24B for E 8B
in E 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm12.98 (d, 2H), 8.07 –
8.01 (m, 1H), 7.97 (s, 1H), 7.82 – 7.68 (m, 4H), 7.65 – 7.53 (m, 4H), 7.51 – 7.31 (m, 4H),
6.95 (d, 1H), 5.41 (s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).
EXAMPLE 25
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
chlorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 25A
1-(2-chlorobenzyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 1-(bromomethyl)chlorobenzene
for EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 25B
tert-butyl benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(2-
chlorobenzyl)-1H-pyrazolyl)picolinate
The title nd was ed by substituting EXAMPLE 25A for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 25C
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
chlorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 25B for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.85 (s, 2H), 8.04 (d,
1H), 7.93 (s, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.61 (d, 2H), 7.52 – 7.27 (m, 7H), 7.01 (dd, 1H),
6.95 (d, 1H), 5.43 (s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).
EXAMPLE 26
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(pyridin
ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 26A
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
(pyridinylmethyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting 2-((4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazolyl)methyl)pyridine for 1-benzyl(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 26B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(pyridin
ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 26A for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.87 (s, 1H), 8.57 (d,
1H), 8.04 (d, 1H), 7.97 (s, 1H), 7.82-7.86 (m, 1H), 7.79 (d, 1H), , 1H), 7.61-7.62 (m,
2H), 7.42-7.50 (m, 2H), 7.34-7.39 (m, 3H), 7.11 (d, 1H), 6.95 (d, 1H), 5.45 (s, 2H), 4.95 (s,
2H), 3.87 (t, 2H), 3.00 (t, 2H).
EXAMPLE 27
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl
cyano-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 27A
1-benzyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazolecarbonitrile
The title compound was prepared by substituting benzyl bromide for EXAMPLE 4A
and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazolecarbonitrile for 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 4B.
E 27B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
cyano-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 27A for 1-benzyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 27C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl
cyano-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 27B for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 1H), 8.15 (s,
1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.66 (d, 1H), 7.62 (d, 1H), 7.43-7.49 (m, 2H), .39 (m,
7H), 7.05 (d, 1H), 5.45 (s, 2H), 5.01 (s, 2H), 3.92 (t, 2H),3.02 (t, 2H).
EXAMPLE 28
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(naphthalen
ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
E 28A
1-(naphthalenylmethyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 2-(bromomethyl)naphthalene for
EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 28B
tert-butyl 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(naphthalenylmethyl)-1H-pyrazolyl]pyridinecarboxylate
The title compound was prepared by substituting EXAMPLE 28A for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 28C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(naphthalen
ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting E 28B for EXAMPLE 1E
in E 1F. 1H NMR (400MHz, dimethylsulfoxide-d 6) G ppm 12.83 (br s, 1H), 8.04 (d,
1H), 7.98 (s, 1H), 7.88 (m, 3H), 7.78 (m, 2H), 7.72 (d, 1H), 7.60 (m, 2H), 7.50 (m, 3H), 7.36
(m, 4H), 6.94 (d, 1H), 5.50 (s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).
EXAMPLE 29
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-(3-methyl-
1,2,4-oxadiazolyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 29A
3-methyl(3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazol
yl)methyl)phenyl)-1,2,4-oxadiazole
The title compound was prepared by substituting 5-(3-(bromomethyl)phenyl)
methyl-1,2,4-oxadiazole for EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 29B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(3-(3-
-1,2,4-oxadiazolyl)benzyl)-1H-pyrazolyl)picolinate
The title nd was prepared by substituting EXAMPLE 29A for E
22A in EXAMPLE 22B.
EXAMPLE 29C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-(3-methyl-
1,2,4-oxadiazolyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 29B for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.85 (m, 2H), 8.08 -
7.97 (m, 4H), 7.79 (d, 1H), 7.72 (d, 1H), 7.65 -7.52 (m, 4H), 7.51 -7.31 (m, 4H), 6.95 (d,
1H), 5.47 (s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H), 2.40 (s, 3H).
EXAMPLE 30
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-benzyl
(hydroxymethyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 30A
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(4,4,5,5-
ethyl-1,3,2-dioxaborolanyl)picolinate
A mixture of EXAMPLE 1D (1.2 g), 1.0 M 4,4,5,5-tetramethyl-1,3,2-dioxaborolane
in tetrahydrofuran (4.24 mL), ylamine (0.92 mL), and [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (0.087 g) in CH3CN
(15 mL) was heated at 100oC in a Biotage Initiator microwave reactor for 30 minutes. After
cooling, the reaction e was partitioned between water and ethyl acetate. The organic
layer was extracted with additional ethyl acetate twice. The combined organic layers were
washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by
flash column tography on silica gel to provide the title compound.
EXAMPLE 30B
ethyl 1-benzylbromomethyl-1H-pyrazolecarboxylate
The title compound was prepared by substituting (1-bromomethyl)benzene for
EXAMPLE 4A and methyl 4-bromomethyl-1H-pyrazolecarboxylate for 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 4B.
EXAMPLE 30C
(1-benzylbromomethyl-1H-pyrazolyl)methanol
EXAMPLE 30B (0.281 g) in tetrahydrofuran (10 mL) was treated with 1.0 M LiAlH4
in tetrahydrofuran (1.0 mL) at 0 ºC. After the reaction was complete, the reaction mixture
was quenched by 1.0 N aqueous HCl. It was then partitioned between water and ethyl
acetate. The c layer was extracted with additional ethyl acetate twice. The combined
organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The
residue was purified by flash column chromatography on silica gel to provide the title
EXAMPLE 30D
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
benzyl(hydroxymethyl)methyl-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 30A for 1-benzyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole and EXAMPLE 30C for
EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 30E
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-benzyl
(hydroxymethyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 30D for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.87 (s, 1H), 8.03 (d,
1H), 7.79 (d, 1H), 7.62 (d, 1H), , 1H), 7.43-7.49 (m, 2H), .39 (m, 7H), .28
(m, 1H), 7.11 (d, 2H), 6.98 (d, 1H), 5.28 (s, 2H), 4.97 (s, 2H), 4.20 (s, 2H), 3.91 (t, 2H), 3.02
(t, 2H), 1.97 (s, 3H).
EXAMPLE 31
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(benzyloxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 31A
1-(benzyloxy)(bromomethyl)benzene
The title compound was prepared by substituting (2-(benzyloxy)phenyl)methanol for
(4-(benzyloxy)phenyl)methanol in EXAMPLE 4A.
EXAMPLE 31B
1-(2-(benzyloxy)benzyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 31A for EXAMPLE 4A
in EXAMPLE 4B.
EXAMPLE 31C
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(2-
(benzyloxy)benzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 31B for 1-benzyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 31D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(benzyloxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 31C for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (s, 1H), 8.04 (d,
1H), 7.79-7.80 (m, 2H), 7.61-7.63 (m, 2H), 7.56 (s, 1H), 7.40-7.50 (m, 4H), 7.25-7.38 (m,
6H), 7.09 (d, 2H), 6.98-7.00 (m, 1H), 6.89-9.94 (m, 2H), 5.32 (s, 2H), 5.17 (s, 2H), 4.95 (s,
2H), 3.87 (t, 2H), 2.98 (t, 2H).
EXAMPLE 32
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-methyl{[6-
(pyrrolidinyl)pyridinyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid and
6-(8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(3-methyl((6-
(pyrrolidinyl)pyridinyl)methyl)-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 32A
2-((5-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazolyl)methyl)
(pyrrolidinyl)pyridine and 2-((3-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-
1H-pyrazolyl)methyl)(pyrrolidinyl)pyridine
The title compounds were ed by tuting 2-(bromomethyl)(pyrrolidin
yl)pyridine for EXAMPLE 4A and 3-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-
azole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE
4B. The title compounds were isolated as a 2:1 mixture of the regioisomeric pyrazole
isomers, and were used in the next step without further purification.
EXAMPLE 32B
tert-butyl 6-(8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(51-((6-(pyrrolidinyl)pyridinyl)methyl)-1H-pyrazolyl) pyridinecarboxylate
and tert-butyl 6-(8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(3-
methyl((6-(pyrrolidinyl)pyridinyl)methyl)-1H-pyrazolyl) pyridinecarboxylate
The titles compound were ed by tuting EXAMPLE 32A fr EXAMPLE
22A in EXAMPLE 22B. The title compounds were ed as a 2:1 mixture of the
regioisomeric pyrazole isomers.
EXAMPLE 32C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-methyl{[6-
(pyrrolidinyl)pyridinyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid and
6-(8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(3-methyl((6-
(pyrrolidinyl)pyridinyl)methyl)-1H-pyrazolyl)pyridinecarboxylic acid
The title compounds were prepared by substituting EXAMPLE 32B for EXAMPLE
8B in EXAMPLE 8C. The title compounds were isolated as a 2:1 mixture of the
someric pyrazole isomers. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.86 (s,
2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.57 – 7.29 (m, 7H), 6.97 (d, 1H), 6.42 (m, 1H),
6.02 (d, 1H), 4.96 (s,2H), 3.89 (m, 2H), 3.39 (d, 4H), 3.17 (s, 2H), 2.99 (m, 2H), 2.17 (s, 3H),
1.93 (m, 4H).
Isomeric Pyrazole: 1H NMR (300 MHz, DMSO) δ 12.86 (s, 2H), 8.04 (d, 1H), 7.79 (d, 1H),
7.69 (s, 1H), 7.62 (d, 1H), 7.57 – 7.29 (m, 6H), 6.97 (d, 1H), 6.42 (m, 1H), 6.02 (d, 1H), 4.96
(s, 2H), 3.89 (m, 2H), 3.39 (d, 4H), 3.17 (s, 2H), 2.99 (m, 2H), 2.04 (s, 3H), 1.93 (m, 4H).
EXAMPLE 33
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-benzyl
(ethoxycarbonyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 33A
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
benzyl(ethoxycarbonyl)methyl-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 30A for ,5,5-
ethyl-1,3,2-dioxaborolanyl)-1H-pyrazole and EXAMPLE 30B for EXAMPLE 1D in
EXAMPLE 1E.
EXAMPLE 33B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-benzyl
ycarbonyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 33A for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.87 (s, 1H), 8.35 (d,
1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.43-7.49 (m, 3H), 7.34-7.38 (m, 4H), 7.30 (d, 1H), 7.12 (d,
2H), 6.99 (d, 1H), 5.44 (s, 2H), 4.99 (s, 2H), .06 (m, 2H), 3.93-3.96 (m, 2H), 3.02 (t,
2H), 2.00 (s, 3H), 1.05 (t, 3H).
EXAMPLE 34
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(dimethylamino)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 34A
N,N-dimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazol
yl)methyl)aniline
To a solution of (3-(dimethylamino)phenyl)methanol (0.100 g), 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (0.167 g) and
cyanomethylenetributylphosphorane (0.208 g) were added and stirred together in e (1
mL) at room temperature. After stirring overnight the reaction was loaded directly onto silica
gel and eluted using a gradient of 5% to 35% ethyl acetate/hexanes to provide the title
compound.
EXAMPLE 34B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(3-
hylamino)benzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 34A for E
22A in EXAMPLE 22B.
EXAMPLE 34C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(dimethylamino)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 34B for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.85 (s, 1H), 8.04 (dd,
1H), 7.88 (d, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.61 (d, 1H), 7.56 (d, 1H), 7.53 – 7.44 (m, 1H),
7.44 – 7.31 (m, 3H), 7.20 – 7.10(m, 1H), 6.94 (d, 1H), 6.67 (d, 2H), 6.53 (t, 1H), 5.24 (s,
2H), 4.94 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H), 2.87 (s, 6H).
EXAMPLE 35
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl
ymethyl-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 33B (0.05 g) in dioxane (2 mL) and methanol (0.5 mL) was treated with
2.0N aqueous NaOH (1 mL). The reaction mixture was heated at 90oC for 1 hours. The
ts were removed under reduced pressure, and the residue was purified by reverse phase
Prep HPLC using Gilson system. The d fractions were combined and freeze-dried to
provide the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 1H),
8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.44-7.49 (m, 3H), 7.34-7.39 (m, 4H), 7.29 (d, 1H),
7.13 (d, 2H), 7.00 (d, 1H), 5.41 (s, 2H), 4.98 (s, 2H), 3.87 (t, 2H) 3.03 (t, 2H), 1.98 (s, 3H).
EXAMPLE 36
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
hydroxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 31D for EXAMPLE 4C
in EXAMPLE 4D. 1H NMR (500 MHz, ylsulfoxide-d 6) G ppm 12.86 (s, 1H), 9.75 (s,
1H), 8.04 (d, 1H), 7.83 (s, 1H), 7.80 (d, 1H), 7.70 (d, 1H), 761 (d, 1H), 7.55 (s, 1H), 7.46-7.50
(m, 1H), 7.42-7.43 (m, 1H), 7.34-7.37 (m, 2H), 7.09-7.13 (m, 1H), 6.90-6.94 (m, 2H), 6.82-
6.64 (m, 1H), 6.72-6.76 (m, 1H), 5.23 (s, 2H), 4.94 (s, 2H), 3.86 (t, 2H), 2.99 (t, 2H).
EXAMPLE 37
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,3-dihydro-
1H-indenyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 37A
1-(2,3-dihydro-1H-indenyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 2,3-dihydro-1H-indenol for (3-
(dimethylamino)phenyl)methanol in EXAMPLE 34A.
EXAMPLE 37B
utyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(2,3-
dihydro-1H-indenyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 37A for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 37C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,3-dihydro-
enyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 37B for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.84 (s, 2H), 8.04 (d,
1H), 7.83 (d, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.61 (d, 1H), 7.56 (d, 1H), 7.53 – 7.44 (m, 1H),
7.44 – 7.31(m, 4H), 7.30 – 7.23 (m, 1H), 7.17 (t, 1H), 7.05 (d, 1H), 6.93 (d, 1H), 5.95 – 5.82
(m, 1H), 4.94 (s, 2H), 3.86 (t, 2H), 3.21 – 3.06 (m, 1H), 3.06 – 2.84 (m, 3H), 2.68 – 2.54 (m,
1H), 2.40 (m 1H).
E 38
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
phenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 38A
1-phenethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 2-phenylethanol for (3-
(dimethylamino)phenyl)methanol in EXAMPLE 34A.
EXAMPLE 38B
utyl6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
phenylethyl)-1H-pyrazolyl]pyridinecarboxylate
The title compound was prepared by substituting EXAMPLE 38A for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 38C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
phenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 38B for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.87 (br s, 1H), 8.04
(d, 1H), 7.80 (d, 1H), 7.73 (s, 1H), 7.64 (d, 1H), 7.61 (d, 1H), 7.54 (s, 1H), 7.48 (m, 1H), 7.42
(d, 1H), 7.36 (t, 2H), 7.26 (m, 2H), 7.18 (m, 2H), 6.94 (d, 1H), 4.94 (s, 2H), 4.32 (t, 2H), 3.86
(t, 2H), 3.09 (t, 2H), 3.00 (t, 2H).
EXAMPLE 39
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,4-dihydro-
2H-chromenyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 39A
1-(chromanyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting chromanol for (3-
(dimethylamino)phenyl)methanol in EXAMPLE 34A.
EXAMPLE 39B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
(chromanyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 39A for EXAMPLE
22A in EXAMPLE 22B.
E 39C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,4-dihydro-
2H-chromenyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting E 39B for E 8B
in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.84 (s, 2H), 8.08 –
7.99 (m, 1H), 7.80 (t, 2H), 7.72 (d, 1H), 7.66 – 7.57 (m, 2H), 7.52 – 7.44 (m, 1H), 7.44 – 7.31
(m, 3H), 7.19 (m, 1H), 6.93 (d, 1H), 6.90 – 6.78 (m, 3H), 5.65 (t, 1H), 4.94 (s, 2H), 4.38 –
4.15 (m, 2H), 3.86 (t, 2H), 3.00 (t, 2H), 2.41 – 2.18 (m, 2H).
EXAMPLE 40
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[2-
(dimethylamino)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 40A
tert-butyl 6-(8-(benzo[d]thiazolyl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)(1-(2-(benzyloxy)benzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 31C for E 4C
in EXAMPLE 6A.
E 40B
utyl 6-(8-(benzo[d]thiazolyl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)(1-(2-hydroxybenzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 40A for EXAMPLE 4C
in EXAMPLE 4D.
EXAMPLE 40C
tert-butyl 6-(8-(benzo[d]thiazolyl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)(1-(2-(2-(dimethylamino)ethoxy)benzyl)-1H-pyrazol
yl)picolinate
The title nd was prepared by substituting EXAMPLE 40B for EXAMPLE 6B
in EXAMPLE 6C.
EXAMPLE 40D
(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[2-
(dimethylamino)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 40C for EXAMPLE 6C
in EXAMPLE 6D. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.87 (s, 1H), 9.64 (s,
1H), 8.04 (d, 1H), 7.86 (s, 1H), 7.80 (d, 1H), 7.71 (d, 1H), 761-7.63 (m, 2H), 7.46-7.50 (m,
2H), 7.42-7.44 (m, 1H), 7.31-7.38 (m, 3H), 7.10 (dd, 1H), 7.07 (d, 1H), 6.94-6.99 (m, 2H),
.37 (s, 2H), 4.35-4.36 (m, 2H), 3.86 (t, 2H), 3.57 (m, 1H), 3.00 (t, 2H), 2.90 (s, 6H).
EXAMPLE 41
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
benzyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 41A
1-(2-fluorobenzyl)methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 3-methyl(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)-1H-pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-
1H-pyrazole and 2-fluorobenzyl bromide for EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 41B
tert-butyl benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(2-
fluorobenzyl)methyl-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 41A for 1-benzyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 41C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
fluorobenzyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 41B for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (500 MHz, ylsulfoxide-d 6) G ppm 12.85 (s, 1H), 8.04 (d,
1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.52 (d, 1H), .49 (m, 2H), 7.32-7.38 (m, 4H), 7.20-7.25
(m, 1H), 7.13-7.17 (m, 1H), 6.96 (d, 1H), .93 (m, 1H), 5.35 (s, 2H), 4.96 (s, 2H), 3.88-
3.91 (m, 2H), 3.01 (t, 2H), 2.12 (s, 3H).
EXAMPLE 42
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 42A
1-(cyclohexylmethyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting (bromomethyl)cyclohexane for
EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 42B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
(cyclohexylmethyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting E 42A for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 42C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 42B for E 8B
in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.85 (s, 2H), 8.04 (d,
1H), 7.79 (d, 1H), 7.74 (d, 1H), 7.68 (s, 1H), 7.61 (d, 1H), 7.52 (s, 1H), 7.51 -7.44 (m, 1H),
7.42 (d, 1H), 7.36 (s, 2H), 6.94 (d, 1H), 4.94 (s, 2H), 3.91 (d, 2H), 3.86 (t, 2H), 3.00 (t, 2H),
1.76 (m, 1H), 1.70 -1.56 (m, 3H), 1.51 (d, 2H), 1.26 -1.02 (m, 3H), 0.92 (m, 2H).
EXAMPLE 43
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 43A
1-(cyclohexylmethyl)methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 5-methyl(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)-1H-pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-
1H-pyrazole and (bromomethyl)cyclohexane for EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 43B
utyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
(cyclohexylmethyl)methyl-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 43A for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 43C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by tuting EXAMPLE 43B for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR (300 MHz, ylsulfoxide-d 6) δ ppm 12.84 (s, 1H), 8.03 (d,
1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.48 (s, 3H), 7.39 -7.31 (m, 2H), 7.26 (s, 1H), 6.94 (d, 1H),
4.95 (s, 2H), 3.86 (s, 4H), 3.01 (t, 2H), 2.10 (s, 3H), 1.88 -1.71 (m, 1H), 1.65 (s, 3H), 1.53 (d,
2H), 1.26 -1.05 (m, 3H), 0.98(t, 2H).
EXAMPLE 44
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-{[3-
(dimethylamino)propyl]amino}nitrobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
N,N-Dimethylpropane-1,3-diamine (50 mg) and EXAMPLE 45B (90 mg) in
tetrahydrofuran (10 mL) were treated with triethylamine (0.1 mL) at 70oC for 2 days. The
reaction mixture was concentrated and the crude residue was ved in a mixture of
dichloromethane (5 mL) and TFA (5 mL). The resulting mixture was d for 12 hours and
concentrated. The residue was purified by reverse phase chromatography, eluting with a
gradient of 40% - 80% acetonitrile in 0.1% TFA water over 40 minutes to provide the title
compound as a TFA salt. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 13.08 (s, 1H),
12.85 (s, 1H), 9.28 (s, 1H), 8.23 (t, 1H), 8.11 (d, 1H), 8.04 (d, 1H), 7.94 (s, 1H), 7.79 (d, 1H),
7.69 (d, 1H), 7.61 (d, 1H), 7.57 (s, 1H), 7.45 -7.52 (m, 2H), 7.40 -7.44 (m, 1H), 7.36 (t, 2H),
7.07 (d, 1H), 6.94 (d, 1H), 5.25 (s, 2H), 4.94 (s, 2H), 3.86 (t, 2H), 3.05 -3.15 (m, 2H), 3.00 (t,
2H), 2.76 (d, 6H), 1.86 -1.98 (m, 2H).
EXAMPLE 45
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-fluoro
nitrobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 45A
1-(4-fluoronitrobenzyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 4-(bromomethyl)fluoro
nitrobenzene for EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 45B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(4-
nitrobenzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 45A for 1-benzyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 45C
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-fluoro
nitrobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 45B for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.84 (s, 1H), 8.10 (dd,
1H), 8.04 (d, 1H), 7.99 (s, 1H), 7.79 (d, 1H), 7.65 -7.73 (m, 2H), 7.54 -7.64 (m, 3H), 7.45 -
7.51 (m, 1H), 7.40 -7.45 (m, 1H), 7.36 (t, 2H), 6.95 (d, 1H), 5.45 (s, 2H), 4.95 (s, 2H), 3.87
(t, 2H), 3.00 (t, 2H).
EXAMPLE 46
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[2-
(morpholinyl)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid
E 46A
tert-butyl 6-(8-(benzo[d]thiazolyl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)(1-(2-(2-morpholinoethoxy)benzyl)-1H-pyrazol
yl)picolinate
The title compound was prepared by substituting EXAMPLE 40B for EXAMPLE 6B
and 2-morpholinoethanol for 2-(dimethylamino)ethanol in EXAMPLE 6C.
EXAMPLE 46B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[2-
(morpholinyl)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 46A for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (500 MHz, ylsulfoxide-d 6) G ppm 12.87 (s, 1H), 8.04 (d,
1H), 7.83 (s, 1H), 7.80 (d, 1H), 7.72 (d, 1H), 7.62 (d, 1H), 7.59 (s, 1H), 7.46-7.50 (m, 1H),
7.42-7.44 (m, 1H), 7.31-7.38 (m, 3H), .09(m, 2H), 6.93-6.99 (m, 2H), 5.35 (s, 2H),
4.95 (s, 2H), 4.38-4.40 (m, 2H), 3.86 (t, 2H), 3.60-3.63 (m, 2H), 3.00 (t, 2H).
EXAMPLE 47
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[3-
(dimethylamino)propoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 47A
utyl 6-(8-(benzo[d]thiazolyl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)(1-(2-(3-(dimethylamino)propoxy)benzyl)-1H-pyrazol
yl)picolinate
The title compound was prepared by substituting EXAMPLE 40B for EXAMPLE 6B
and 3-(dimethylamino)propanol for 2-(dimethylamino)ethanol in EXAMPLE 6C.
EXAMPLE 47B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[3-
(dimethylamino)propoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 47A for EXAMPLE 1E
in EXAMPLE 1F. 1HNMR (500 MHz, ylsulfoxide-d 6) G ppm 12.86 (s, 1H), 9.38 (s,
1H), 8.04 (d, 1H), 7.82 (s, 1H), 7.80 (d, 1H), 7.71 (d, 1H), 7.62 (d, 1H), 7.59 (s, 1H), 7.46-
7.50 (m, 1H), 7.42-7.44 (m, 1H), 7.35-7.38 (m, 2H), 7.29-7.32 (m, 1H), 7.06 (dd, 1H), 7.01
(d, 1H), 6.92-6.95 (m, 2H), 5.30 (s, 2H), 4.94 (s, 2H), 4.08 (t, 2H), 3.86 (t, 2H), 3.21-3.25 (m,
2H), 3.00 (t, 2H), 2.80 (s, 6H), 2.09-2.14 (m, 2H).
EXAMPLE 48
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(pyridin
ylmethoxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
E 48A
tert-butyl 6-(8-(benzo[d]thiazolyl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)(1-(2-(pyridinylmethoxy)benzyl)-1H-pyrazol
yl)picolinate
The title compound was prepared by substituting EXAMPLE 40B for E 6B
and pyridinylmethanol for 2-(dimethylamino)ethanol in EXAMPLE 6C.
EXAMPLE 48B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(pyridin
ylmethoxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 48A for EXAMPLE 1E
in EXAMPLE 1F. 1HNMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.84 (s, 1H), 9.38 (s,
1H), 8.71 (d, 2H), 8.04 (d, 1H), 7.84 (s, 1H), 7.79 (d, 1H), 7.72 (d, 2H), 7.67 (d, 1H), 7.61 (d,
1H), 7.59 (s, 1H), 7.46-7.50 (m, 1H), .43 (m, 1H), 7.34-7.38 (m, 2H), 7.27-7.32 (m,
1H), 7.04-7.09 (m, 2H), 6.96-6.98 (m, 1H), 6.93 (d, 1H), 5.41 (s, 2H), 5.38 (s, 2H), 4.94 (s,
2H), 3.86 (t, 2H), 2.99 (t, 2H).
E 49
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[2-
(dimethylamino)ethoxy]benzyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 49A
1-(2-(benzyloxy)benzyl)methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazole
The title compound was prepared by substituting yl(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)-1H-pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-
1H-pyrazole and EXAMPLE 31A for EXAMPLE 4A in EXAMPLE 4B. The desired product
was isolated via Prep HPLC using a Gilson system.
E 49B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(2-
(benzyloxy)benzyl)methyl-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 49A for 1-benzyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 49C
tert-butyl 6-(8-(benzo[d]thiazolyl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)(1-(2-(benzyloxy)benzyl)methyl-1H-pyrazol
yl)picolinate
The title compound was prepared by substituting EXAMPLE 49B for EXAMPLE 4C
in EXAMPLE 6A.
EXAMPLE 49D
tert-butyl benzo[d]thiazolyl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)(1-(2-hydroxybenzyl)methyl-1H-pyrazolyl)picolinate
The title nd was prepared by substituting EXAMPLE 49C for EXAMPLE 4C
in EXAMPLE 4D.
E 49E
tert-butyl 6-(8-(benzo[d]thiazolyl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)(1-(2-(2-(dimethylamino)ethoxy)benzyl)methyl-1H-
pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 49D for EXAMPLE 6B
in EXAMPLE 6C.
EXAMPLE 49F
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[2-
(dimethylamino)ethoxy]benzyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting E 49E for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 1H), 9.67 (s,
1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.55-7.64 (m, 2H), 7.52 (d, 1H), 7.43-7.50 (m, 3H), .39
(m, 3H), 7.07 (d, 1H), 6.93-6.98 (m, 2H), 6.77 (dd, 1H), 5.34 (s, 2H), 4.96 (s, 2H), 4.36-4.39
(m, 2H), 3.89 (t, 2H), 3.58 (d, 2H), 3.01 (t, 2H), 2.93 (d, 6H), 2.09 (s, 3H).
EXAMPLE 50
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(tetrahydro-
2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
E 50A
1-((tetrahydro-2H-pyranyl)methyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
The title compound was ed by substituting (tetrahydro-2H-pyranyl)methanol
for methylamino)phenyl)methanol in E 34A.
EXAMPLE 50B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)
(1-((tetrahydro-2H-pyranyl)methyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 50A for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 50C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(tetrahydro-
2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title nd was prepared by substituting EXAMPLE 50B for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.85 (s, 2H), 8.06 -
8.01 (m, 1H), 7.79 (d, 1H), 7.76 (d, 1H), 7.69 (d, 1H), 7.61 (d, 1H), 7.53 (d, 1H), 7.51 -7.44
(m, 1H), 7.42 (d, 1H), 7.39 -7.32 (m, 2H), 6.94 (d, 1H), 4.94 (s, 2H), 3.99 (d, 2H), 3.83 (dt,
4H), 3.24 (td, 2H), 3.00 (t, 2H), 2.01 (ddd, 1H), 1.46 -1.31 (m, 2H), 1.22 (dd, 2H).
EXAMPLE 51
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[3-
(dimethylamino)propynyl]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 51A
1-(2-bromobenzyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 1-bromo(bromomethyl)benzene
for EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 51B
N,N-dimethyl(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazol
yl)methyl)phenyl)propynamine
EXAMPLE 51A (0.11 g), N,N-dimethylpropynamine (0.1 g),
tetrakis(triphenylphosphine)palladium(0) (0.05 g), copper(I) iodide (0.01 g) and ylamine
(0.3 mL) were suspended in N,N-dimethylformamide (2 mL) in a 5 mL microwave tube. The
mixture was heated at 110 °C in a microwave reactor (Biotage, Iniator) for 30 minutes.
Additional tetrakis(triphenylphosphine)palladium(0) (0.05 g) was added, and the mixture was
heated in a microwave reactor (Biotage, Iniator) at 120ºC for 1 hour. The crude product was
filtered and purified by PrepHPLC (Gilson, C18, Phenomenex®, 250x21.2mm column) and
was eluted with 30-100% CH3CN/water with 0.1% TFA to provide the title compound.
EXAMPLE 51C
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(2-(3-
(dimethylamino)propynyl)benzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 51B for 1-benzyl
,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 51D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[3-
(dimethylamino)propynyl]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 51C for E 1E
in EXAMPLE 1F. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (m, 1H), 8.04 (d,
1H), 7.92 (m, 1H), 7.80 (d, 1H), 7.71 (d, 1H), 7.59 (m, 3H), 7.41 (m, 7H), 7.12 (d, 1H), 6.94
(d, 1H), 5.50 (s, 2H), 4.95 (s, 2H), 4.38 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H), 2.89 (s, 6H).
EXAMPLE 52
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,3-
robenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 52A
1-(2,3-difluorobenzyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 1-(bromomethyl)-2,3-
difluorobenzene for EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 52B
tert-butyl 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,3-
robenzyl)-1H-pyrazolyl]pyridinecarboxylate
The title compound was prepared by substituting EXAMPLE 52A for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 52C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,3-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by tuting EXAMPLE 52B for EXAMPLE 7D
in EXAMPLE 7E. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.87 (br s, 1H), 8.04
(d, 1H), 7.94 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.61 (d, 1H), 7.59 (s, 1H), 7.48 (t, 1H), 7.42
(d, 1H), 7.36 (m, 3H), 7.19 (m, 1H), 7.01 (m, 1H), 6.94 (d, 1H), 5.44 (s, 2H), 4.95 (s, 2H),
3.87 (t, 2H), 3.00 (t, 2H).
EXAMPLE 53
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,5-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 53A
1-(3,5-difluorobenzyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 1-(bromomethyl)-3,5-
difluorobenzene for E 4A in E 4B.
EXAMPLE 53B
tert-butyl 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,5-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylate
The title compound was prepared by substituting EXAMPLE 53A for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 53C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,5-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 53B for E 7D
in EXAMPLE 7E. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (br s, 1H), 8.04
(d, 1H), 7.96 (s, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.62 (d, 1H), 7.61 (s, 1H), 7.48 (t, 1H), 7.43
(d, 1H), 7.36 (t, 2H), 7.17 (m, 1H), 6.94 (d, 1H), 6.92 (m, 2H), 5.38 (s, 2H), 4.95 (s, 2H), 3.87
(t, 2H), 3.00 (t, 2H).
EXAMPLE 54
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,5-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 54A
1-(2,5-difluorobenzyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 1-(bromomethyl)-2,5-
difluorobenzene for EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 54B
tert-butyl 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,5-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylate
The title compound was prepared by substituting EXAMPLE 54A for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 54C
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,5-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 54B for EXAMPLE 7D
in EXAMPLE 7E. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.87 (br s, 1H), 8.04
(d, 1H), 7.94 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.62 (d, 1H), 7.60 (s, 1H), 7.48 (t, 1H), 7.43
(d, 1H), 7.36 (t, 2H), 7.29 (m, 1H), 7.22 (m, 1H), 7.00 (m, 1H), 6.95 (d, 1H), 5.39 (s, 2H),
4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).
EXAMPLE 55
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,6-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 55A
1-(2,6-difluorobenzyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting momethyl)-2,6-
difluorobenzene for E 4A in EXAMPLE 4B.
EXAMPLE 55B
tert-butyl 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,6-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylate
The title compound was prepared by substituting EXAMPLE 55A for EXAMPLE
22A in E 22B.
EXAMPLE 55C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,6-
difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 55B for EXAMPLE 7D
in EXAMPLE 7E. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (br s, 1H), 8.04
(d, 1H), 7.87 (s, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.61 (d, 1H), 7.53 (s, 1H), 7.48 (m, 2H), 7.42
(d, 1H), 7.36 (t, 2H), 7.14 (t, 2H), 6.93 (d, 1H), 5.37 (s, 2H), 4.94 (s, 2H), 3.87 (t, 2H), 3.00 (t,
2H).
EXAMPLE 56
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(tetrahydro-
2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 56A
1-((tetrahydro-2H-pyranyl)methyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazole
The title compound was prepared by substituting (tetrahydro-2H-pyranyl)methanol
for (3-(dimethylamino)phenyl)methanol in EXAMPLE 34A.
EXAMPLE 56B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
ahydro-2H-pyranyl)methyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting E 56A for EXAMPLE
22A in EXAMPLE 22B.
E 56C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(tetrahydro-
2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by tuting EXAMPLE 56B for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.85 (s, 2H), 8.07 -
8.01 (m, 1H), 7.76 (d, 1H), 7.69 (d, 1H), 7.61 (d, 1H), 7.53 (d, 1H), 7.51 -7.44 (m, 1H), 7.43
(d, 1H), 7.35 (dd, 3H), 6.94 (d, 1H), 4.94 (s, 2H), 4.00 (dd, 2H), 3.87 (t, 2H), 3.75 -3.64 (m,
1H), 3.60 (dd, 1H), 3.38 -3.26 (m,1H), 3.14 (dd, 1H), 3.00 (t, 2H), 2.02 (s, 1H), 1.61 (dd,
2H), 1.52 -1.34 (m, 1H), 1.21 (d, 1H).
EXAMPLE 57
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
nitrobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 57A
1-(2-nitrobenzyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 1-(bromomethyl)nitrobenzene for
EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 57B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(2-
nitrobenzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 57A for 1-benzyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 57C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
nitrobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was ed by substituting EXAMPLE 57B for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (s, 1H), 8.09 (dd,
1H), 8.03 (d, 1H), 7.95 (s, 1H), 7.75 (m, 3H), 7.47 (m, 8H), 6.96 (d, 1H), 6.87 (dd, 1H), 5.72
(s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).
EXAMPLE 58
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(biphenyl
yl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 58A
1-Biphenylylmethyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-1H-pyrazole
The title compound was prepared by tuting 3-(bromomethyl)biphenyl for
EXAMPLE 4A in EXAMPLE 4B.
E 58B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(biphenyl
ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid tert-butyl ester
EXAMPLE 58A (76 mg) and EXAMPLE 1D (100 mg) were added to 1,4-dioxane
(1.5 mL). 2M aqueous sodium ate (0.265 mL) was added. The on was degassed
and flushed with nitrogen three times. Dichloro[1,1’-
bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (14 mg) was added.
The solution was ed and flushed with nitrogen and then heated at 70°C for 16 hours.
The solution was cooled, added to water, extracted with 50% ethyl acetate in hexanes, washed
with brine, dried on anhydrous sodium sulfate, and concentrated under vacuum. The crude
material was purified on silica gel using 30-50% ethyl acetate in hexanes.
EXAMPLE 58C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(biphenyl
ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by tuting E 58B for EXAMPLE 7D
in EXAMPLE 7E. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.84 (bs, 1H), 8.04 (d,
1H), 7.98 (d, 1H), 7.80 (d, 1H), 7.72 (d, 1H), 7.66-7.53 (m, 6H), 7.51-7.32 (m, 8H), 7.23 (d,
1H), 6.95 (d, 1H), 5.40 (s, 2H), 4.94 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).
EXAMPLE 59
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,2-
dimethylpropyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 59A
1-neopentyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 2,2-dimethylpropanol for (3-
(dimethylamino)phenyl)methanol in E 34A.
EXAMPLE 59B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
neopentyl-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 59A for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 59C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,2-
dimethylpropyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 59B for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 13.08 -12.70 (m, 1H),
8.04 (dd, 1H), 7.79 (d, 1H), 7.71 (dd, 2H), 7.66 -7.58 (m, 1H), 7.53 (d, 1H), 7.52 -7.45 (m,
1H), 7.45 - 7.31 (m, 3H), 6.94 (d, 1H), 4.94 (s, 2H), 3.94 - 3.79 (m, 4H), 3.00 (t, 2H), 0.89 (s,
9H).
EXAMPLE 60
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
exylethyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 60A
1-(2-cyclohexylethyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting (2-bromoethyl)cyclohexane for
EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 60B
tert-butyl 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
cyclohexylethyl)-1H-pyrazolyl]pyridinecarboxylate
The title compound was prepared by substituting EXAMPLE 60A for EXAMPLE
22A in EXAMPLE 22B.
E 60C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-
cyclohexylethyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 60B for EXAMPLE 7D
in EXAMPLE 7E. 1H NMR z, dimethylsulfoxide-d 6) G 12.87(br s, 1H), 8.04 (d,
1H), 7.80 (s, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.61 (d, 1H), 7.51 (s, 1H), 7.48 (m, 1H), 7.42 (d,
1H), 7.36 (t, 2H), 6.94 (d, 1H), 4.95 (s, 2H), 4.10 (t, 2H), 3.87 (t, 2H), 3.00 (t, 2H), 1.66 (m,
7H), 1.15 (m, 4H), 0.90 (m, 2H).
EXAMPLE 61
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(trifluoromethyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 61A
1-[3-(trifluoromethyl)benzyl](4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 1-(bromomethyl)
(trifluoromethyl)benzene for EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 61B
tert-butyl 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(trifluoromethyl)benzyl]-1H-pyrazolyl}pyridinecarboxylate
The title compound was prepared by substituting EXAMPLE 61A for EXAMPLE
22A in E 22B.
E 61C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(trifluoromethyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by tuting EXAMPLE 61B for EXAMPLE 7D
in EXAMPLE 7E. 1H NMR (400MHz, dimethylsulfoxide-d 6) G 12.85 (br s, 1H), 8.04 (d,
1H), 8.00 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.62 (d, 1H), 7.61 (m, 4H), 7.48 (m, 3H), 7.36 (t,
2H), 6.94 (d, 1H), 5.45 (s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).
E 62
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(biphenyl
ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 62A
1-Biphenylylmethyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-1H-pyrazole
The title nd was prepared by substituting 2-(bromomethyl)biphenyl for
EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 62B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(biphenyl
ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid tert-butyl ester
The title compound was prepared by tuting EXAMPLE 62A for EXAMPLE
58A in EXAMPLE 58B.
EXAMPLE 62C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(biphenyl
ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 62B for EXAMPLE 7D
in EXAMPLE 7E. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (bs, 1H), 8.04 (d,
1H), 7.80 (d, 1H), 7.68-7.65 (m, 2H), 7.72 (d, 1H), 7.61 (d, 1H), .31 (m, 11H), 7.26
(dd, 1H), 7.07 (dd, 1H), 6.94 (d, 1H), 5.26 (s, 2H), 4.94 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).
EXAMPLE 63
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclopentylmethyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 63A
1-(cyclopentylmethyl)-1H-pyrazole
A flask was charged with pyrazole (380 mg), (bromomethyl)cyclopentane (968 mg),
tetrabutylammonium bromide (18 mg), 50% aqueous NaOH (0.6 mL) and toluene (1.5 mL)
and the mixture was heated to 110oC for 4.5 hours. The reaction mixture was cooled to room
temperature and partitioned between toluene (3x 10 mL) and H2O (10 mL). The extracts were
dried (MgSO4), filtered, and concentrated to give the title compound.
EXAMPLE 63B
1-(cyclopentylmethyl)methyl-1H-pyrazole
A solution of E 63A (727 mg) in tetrahydrofuran (10 mL) was chilled to -
45oC. n-Butyllithium (2.3 M solution in hexanes, 2.52 mL) was added dropwise over 5
minutes. The reaction was stirred for 1.5 hours, during which time the temperature sed
to -20oC. Iodomethane (0.368 mL) was added dropwise over 3 minutes. The reaction was
stirred for 30 minutes between -20 and -15oC. Water (25 mL) was added and the mixture was
extracted with ethyl acetate (3 x 25 mL). The extracts were dried (Na2SO4), filtered, and
concentrated to provide the title compound.
EXAMPLE 63C
4-bromo(cyclopentylmethyl)methyl-1H-pyrazole
EXAMPLE 63B (570 mg) was ved in N,N-dimethylformamide (5 mL) and N-
bromosuccinimide (649 mg) was added. The reaction was stirred at room temperature for 2.5
hours. 10% Aqueous Na2S2O3 (10 mL) and water (20 mL) were added and the reaction was
extracted with ethyl acetate (3 x 25 mL). The combined extracts were dried (Na2SO4),
ed, and concentrated. Silica gel chromatography (gradient from 0 to 10% ethyl e-
s over 25 minutes) provided the title compound.
EXAMPLE 63D
1-(cyclopentylmethyl)methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
EXAMPLE 63C (220 mg), bis(pinacolato)diboron (276 mg) and potassium acetate
(240 mg) were combined in methylformamide (3 mL) and the mixture was ed
with N2. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (44 mg) was added,
the reaction vessel was sealed, and the mixture was heated to 90oC for 18 hours. The reaction
mixture was partitioned between H2O (15 mL) and ethyl acetate, and the aqueous layer was
extracted with ethyl acetate (3 x 10 mL). The extracts were dried (Na2SO4), filtered, and
concentrated, and the residue was purified by flash tography (gradient from 0 to 10%
ethyl acetate/hexanes) to provide the title compound.
EXAMPLE 63E
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
(cyclopentylmethyl)methyl-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 63D for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 63F
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclopentylmethyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 63E for EXAMPLE 8B
in E 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.70 -12.88 (m, 2H),
8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.41 -7.52 (m, 3H), 7.32 -7.39 (m, 2H), 7.25 (s, 1H),
6.94 (d, 1H), 4.95 (s, 2H), 3.94 (d, 2H), 3.89 (t, 2H), 3.01 (t , 2H), 2.28 - 2.38 (m, 1H), 2.12
(s, 3H), 1.42 - 1.66 (m, 6H), 1.20 - 1.32 (m, 2H).
EXAMPLE 64
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
formylbenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 64A
3-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolanyl)-pyrazolylmethyl]-benzaldehyde
The title compound was prepared by substituting 3-(bromomethyl)benzaldehyde for
EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 64B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
formylbenzyl)-1H-pyrazolyl]pyridinecarboxylic acid tert-butyl ester
The title compound was prepared by substituting EXAMPLE 64A for EXAMPLE
58A in EXAMPLE 58B.
EXAMPLE 64C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
formylbenzyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 64B for EXAMPLE 7D
in E 7E. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (bs, 1H), 9.98 (s,
1H), 8.04 (d, 1H), 7.98 (s, 1H), .78 (m, 3H), 7.72 (d, 1H), 7.63-7.54 (m, 3H), 7.51-7.32
(m, 5H), 6.95 (d, 1H), 5.45 (s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).
EXAMPLE 65
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl
phenyl-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 65A
ethyl 2-(2-phenyl-1,3-dioxolanyl)acetate
A solution of ethyl 3-oxophenylpropanoate (23.74 g) in toluene, ethyleneglycol
(23.04 g), and p-toluenesulfonic acid (200 mg) in toluene (300 mL) was d under reflux
with a Dean-Stark trap for 15 hours. The cooled mixture was poured onto saturated aqueous
sodium bicarbonate (100 mL) and the organic layer was washed with water, brine and dried
over Na2SO4. Filtration and evaporation of t provided the title compound which was
used in the next reaction t r purification.
EXAMPLE 65B
2-(2-phenyl-1,3-dioxolanyl)acetaldehyde
To a solution of EXAMPLE 65A (2.36 g) in toluene (30 mL) was added
diisobutylaluminium e (1.5M in toluene, 8 mL) at -78oC. After stirring for 10 minutes
the reaction mixture was quenched by addition of water. The precipitate was removed by
filtration through diatomaceous earth. The filtrate was washed with water and brine and dried
over Na2SO4. Filtration and evaporation of t provided the title compound.
EXAMPLE 65C
tert-butyl 1-benzyl(2-(2-phenyl-1,3-dioxolanyl)ethyl)hydrazinecarboxylate
To a solution of tert-butyl 1-benzylhydrazinecarboxylate (2.3 g, prepared according to
Eur. J. Org. Chem. 2010, 3815-3822) and EXAMPLE 65B (2 g) in dichloromethane (30 mL)
was added sodium triacetoxyborohydride (3.3 g). The mixture was stirred at room
temperature. overnight. The mixture was d with ethyl acetate (300 mL) and washed
with aqueous NaOH, water, and brine and dried over Na2SO4. Filtration and evaporation of
solvent gave the expected product.
EXAMPLE 65D
tert-butyl 1-benzyl(3-oxophenylpropyl)hydrazinecarboxylate
To a on of EXAMPLE 65C (3.86 g) in acetone (5 mL) and water (5 mL) was
added pyridinium p-toluenesulfonate(120 mg). The mixture was stirred at 100oC in a
e tor microwave reactor for 10 minutes. The mixture was d with ethyl
acetate (200 mL) and washed with water and brine and dried over Na2SO4. Filtration and
evaporation of the solvent gave the crude product which was used without further purification
in the next reaction.
EXAMPLE 65E
1-benzylphenyl-1H-pyrazole
To a solution of EXAMPLE 65D (3.1 g) in dichloromethane (10 mL) was added TFA
(10 mL) and the mixture was stirred overnight. The mixture was trated under vacuum
and the residue was dissolved in ethyl e (300 mL) and washed with 2N aqueous NaOH,
water and brine. The combined organic layers were trated, and the residue was
dissolved in dichloroethane (30 mL) and MnO2 (2.5 g) was added. The mixture was stirred
overnight. .Filtration and evaporation of the solvent provided the title compound.
EXAMPLE 65F
1-benzyliodophenyl-1H-pyrazole
To a solution of EXAMPLE 65E (270 mg) in N,N-dimethylformamide (5 mL) was
added N-iodosuccinimide (259 mg). The mixture was stirred overnight. The mixture was
diluted with ethyl acetate (200 mL) and washed with aqueous sodium bisulfite, water, and
brine. The organic layers were combined, and evaporation of the t provided the title
compound.
EXAMPLE 65G
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl
phenyl-1H-pyrazolyl)pyridinecarboxylic acid
To a mixture of EXAMPLE 30A (200 mg) and EXAMPLE 65F (118 mg) in dioxane
(9 mL) was added tetrakis(triphenylphosphine)palladium(0) (19 mg) and saturated aqueous
NaHCO3 (3 mL). The mixture was purged with argon and stirred at 120°C in a Biotage
Initiator microwave reactor for 30 minutes. The e was diluted with ethyl acetate (200
mL) and washed with water and brine and dried over Na2SO4. tion and evaporation of
the solvent gave crude product which was loaded on a silica gel cartridge and eluted with 20%
ethyl acetate in dichloromethane to give the crude product which was dissolved in
dichloromethane (3 mL) and TFA (3 mL) and stirred overnight. After evaporation of the
solvent, the e was loaded on a silica gel dge and eluted with 5% methanol in
dichloromethane to provide the title compound. 1H NMR (300 MHz, CDCl 3) G ppm 7.91 (dd,
3H), 7.75 (s, 1H), 7.64 (t, 1H), 7.54 (t, 1H), 7.48 (m, 2H), 7.35 (d, 1H), 7.29 (m, 8H), 7.14 (m,
2H), 7.07 (m, 2H), 6.81 (d, 1H), 5.36 (s, 2H), 5.20 (s, 1H), 3.78 (t, 2H), 3.11 (t, 2H)
EXAMPLE 66
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl
(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 66A
1-((tetrahydro-2H-pyranyl)methyl)-1H-pyrazole
The title compound was prepared by substituting (tetrahydro-2H-pyranyl)methanol
for (3-(dimethylamino)phenyl)methanol and 1H-pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 66B
-methyl((tetrahydro-2H-pyranyl)methyl)-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 66A for EXAMPLE
63A in EXAMPLE 63B.
EXAMPLE 66C
4-iodomethyl((tetrahydro-2H-pyranyl)methyl)-1H-pyrazole
The title compound was prepared by substituting E 66B for EXAMPLE
65E in E 65F.
EXAMPLE 66D
tert-butyl benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(5-
methyl((tetrahydro-2H-pyranyl)methyl)-1H-pyrazolyl)picolinate
A mixture of EXAMPLE 30A (0.220 g), EXAMPLE 66C (0.100 g) and
tetrakis(triphenylphosphine)palladium(0) (0.019 g) was added dioxane (3 mL) and saturated
aqueous NaHCO3 solution (2 mL). The on was degassed with nitrogen then heated to
120°C for 30 minutes. The mixture was partioned between ethyl acetate (75 mL) and water
(75 mL) and filtered to remove solids. The organic layer was dried over magnesium sulfate,
filtered, and concentrated. Silica gel chromatography, eluting with a gradient of 0.5% to
3.0% methanol/dichloromethane, provided the title compound.
EXAMPLE 66E
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl
(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 66D for E 8B
in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.84 (s, 1H), 8.03 (d,
1H), 7.79 (d, 1H), 7.61 (d1H), 7.52 -7.40 (m, 3H), 7.40 -7.31 (m, 2H), 7.27 (s, 1H), 6.95 (d,
1H), 4.96 (d, 2H), 3.93 (ddd, 3H), 3.75 -3.64 (m, 1H), 3.59 (dd, 1H), 3.46 -3.29 (m, 1H),
3.16 (s, 1H), 3.01 (s, 2H), 2.11 (s, 3H), 2.02 (s, 1H), 1.81 -1.52 (m, 2H), 1.45 (ddd, 1H), 1.37
-1.17 (m, 2H).
EXAMPLE 67
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-
phenylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid
E 67A
(1-phenylcyclohexyl)methanol
To a solution of 1-phenylcyclohexanecarboxylic acid (1.32 g) in tetrahydrofuran (30
mL) at 0oC was slowly added 2 M LiAlH4 in tetrahydrofuran (6.46 mL). The ing
mixture was stirred at room temperature overnight and cooled to 0oC. Ice water was added to
quench the reaction. The ing e was diluted with ethyl acetate and washed with 1
N aqueous NaOH and water. The organic layer was dried over Na2SO4, filtered, and
concentrated to provide the title compound.
EXAMPLE 67B
1-((1-phenylcyclohexyl)methyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 67A for (3-
hylamino)phenyl)methanol in EXAMPLE 34A.
EXAMPLE 67C
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((1-
phenylcyclohexyl)methyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 67B for yl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 67D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-
phenylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 67C for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (s, 2H), 8.04 (d,
1H), 7.80 (d, 1H), 7.61 (d, 1H), 7.39 -7.51 (m, 4H), 7.32 -7.39 (m, 2H), 7.25 -7.32 (m, 2H),
7.14 - 7.24 (m, 3H), 6.87 - 6.94 (m, 2H), 4.92 (s, 2H), 4.11 (s, 2H), 3.85 (t, 2H), 2.98 (t, 2H),
2.13 (s, 2H), 1.51 - 1.65 (m, 4H), 1.42 (s, 1H), 1.16 - 1.33 (m, 3H).
E 68
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{3-
[(dimethylamino)methyl]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 68A
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{3-
[(dimethylamino)methyl]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid tert butyl ester
EXAMPLE 64B (100 mg) was dissolved in dichloromethane (1 mL). Dimethylamine
(2M, 0.373 mL) was added, and the solution was stirred at room temperature for 15 s.
Sodium toxyborohydride (38 mg) was then added, and the solution was stirred at room
temperature for 16 hours. After this time more dimethylamine (2M, 0.373 mL) and sodium
triacetoxyborohydride (38 mg) was added, and the solution was stirred for r 16 hours.
The crude material was then purified on silica gel using 20% methanol (dichloromethane).
EXAMPLE 68B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{3-
[(dimethylamino)methyl]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 68A for EXAMPLE 7D
in EXAMPLE 7E to isolate the title compound as the mono trifluoroacetic acid salt. 1H NMR
(400 MHz, dimethylsulfoxide-d 6) G ppm 12.84 (bs, 1H), 9.57 (bs, 1H), 8.04 (d, 1H), 7.92 (s,
1H), 7.80 (d, 1H), 7.71 (d, 1H), 7.64-7.57 (m, 2H), 7.51-7.32 (m, 8H),6.95 (d, 1H), 5.37 (s,
2H), 4.95 (s, 2H), 4.25 (d, 2H), 3.87 (t, 2H), 3.00 (t, 2H), 2.71 (s, 3H), 2.70 (s, 3H).
EXAMPLE 69
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(methylsulfonyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 69A
1-(3-methanesulfonyl-benzyl)(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 1-(bromomethyl)
(methylsulfonyl)benzene for EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 69B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
lsulfonyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid tert-butyl ester
The title compound was prepared by substituting EXAMPLE 69A for EXAMPLE
58A in EXAMPLE 58B.
E 69C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-
(methylsulfonyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 69B for E 7D
in EXAMPLE 7E. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (bs, 1H), 8.04 (d,
1H), 7.99 (s, 1H), 7.89-7.84 (m, 3H), 7.78 (s, 1H), 7.72 (d, 1H), 7.65-7.61 (m, 3H), 7.56-7.37
(m, 4H), 6.96 (d, 1H), 5.47 (s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.20 (s, 3H), 3.00 (t, 2H).
EXAMPLE 70
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)cyclopropyl-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 70A
2-(5-cyclopropyl-1H-pyrazolyl)isoindoline-1,3-dione
5-Cyclopropyl-1H-pyrazolamine (5 g) was slurried in dioxane (80 mL) and N,N-
dimethylformamide (80 mL), then phthalic anhydride (6 g) was added and the on was
heated at 120°C for 4 days. The reaction was cooled and concentrated. The crude material
was triturated with isopropyl ether/ethanol 1/1 (30 mL) to provide the title compound.
EXAMPLE 70B
cyclohexylmethyl)cyclopropyl-1H-pyrazolyl)isoindoline-1,3-dione
EXAMPLE 70A (4.5 g) was ved in N,N-dimethylformamide (77 mL), then
(bromomethyl)cyclohexane (4.0 g) was added, followed by 95% sodium hydride (0.6 g). The
reaction was heated at 70°C for 2 hours. The reaction mixture was then cooled, diluted with
water and extracted with ethyl acetate. The c layer was washed with brine and the
combined aqueous layerswere xtracted with ethyl e. The combined organic
layers were dried over Na2SO4. The crude material was purified by column chromatography
on silica gel using 0-4% ethyl acetate in dichloromethane to give a e of the title
compound and the 3-cyclopropyl isomer.
EXAMPLE 70C
1-(cyclohexylmethyl)cyclopropyl-1H-pyrazolamine
EXAMPLE 70B (1.4 g) was dissolved in ethanol (70 mL) then hydrazine hydrate (1.1
mL) was added and the reaction heated under reflux for 40 minutes. The reaction was then
cooled and filtered, and the filtrate was concentrated to give the crude product. The title
compound was isolated by column chromatography on silica gel using 0.5-2.0% methanol in
dichloromethane.
EXAMPLE 70D
1-(cyclohexylmethyl)cyclopropyl-1H-pyrazole
E 70C (415 mg) was dissolved in tetrahydrofuran (12 mL), then isoamyl
nitrite (774 mg) was added and the reaction was heated at 60°C overnight. The reaction was
then cooled, concentrated, and purified by column chromatography on silica gel using 85/15
hexanes/ethyl acetate.
EXAMPLE 70E
4-bromo(cyclohexylmethyl)cyclopropyl-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 70D for EXAMPLE
63B in EXAMPLE 63C.
EXAMPLE 70F
1-(cyclohexylmethyl)cyclopropyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazole
The title compound was prepared by substituting EXAMPLE 70E for EXAMPLE
84C in E 84D, except the crude product was purified by column chromatography
on silica gel using 5-12% ethyl acetate in hexanes.
EXAMPLE 70G
tert-butyl 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)cyclopropyl-1H-pyrazolyl]pyridinecarboxylate
The title compound was ed by tuting EXAMPLE 70F for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 70H
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)cyclopropyl-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting E 70G for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR z, dimethylsulfoxide-d 6) G ppm 12.85 (br s, 1H), 8.03
(d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.54 (d, 1H), 7.45 (m, 2H), 7.36 (m, 2H), 7.22 (s, 1H),
6.93 (d, 1H), 4.96 (s, 2H), 3.97 (d, 2H), 3.89 (t, 2H), 3.01 (t, 2H), 1.60-1.69 (m, 7H), 1.16 (m,
3H), 0.98 (m, 2H), 0.79 (m, 2H), 0.25 (m, 2H).
EXAMPLE 71
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,5-di-tertbutylbenzyl
)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 71A
1-(3,5-di-tert-butylbenzyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting 1-(bromomethyl)-3,5-di-tert-
enzene for EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 71B
tert-butyl 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,5-
di-tert-butylbenzyl)-1H-pyrazolyl]pyridinecarboxylate
The title compound was prepared by substituting EXAMPLE 71A for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 71C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,5-di-tertbutylbenzyl
)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 71B for E 7D
in EXAMPLE 7E. 1H NMR (400MHz, dimethylsulfoxide-d 6) G ppm 12.86 (br s, 1H), 8.04
(d, 1H), 7.93 (s, 1H), 7.79 (d, 1H), 7.69 (d, 1H), 7.61 (d, 1H), 7.58 (s, 1H), 7.48 (m, 1H), 7.43
(d, 1H), 7.36 (t, 2H), 7.29 (m, 1H), 7.05 (d, 2H), 6.94 (d, 1H), 5.29 (s, 2H), 4.95 (s, 2H), 3.87
(t, 2H), 3.00 (t, 2H), 1.24 (s, 18H).
EXAMPLE 72
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(morpholin-
lfonyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 72A
4-{2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolanyl)-pyrazolylmethyl]-
benzenesulfonyl}-morpholine
The title compound was ed by substituting 1-(bromomethyl)
(phenylsulfonylmethyl)benzenefor EXAMPLE 4A in E 4B.
EXAMPLE 72B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(morpholin-
4-ylsulfonyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid tert-butyl ester
The title compound was prepared by substituting E 72A for EXAMPLE
58A in EXAMPLE 58B.
EXAMPLE 72C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(morpholin-
4-ylsulfonyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 72B for EXAMPLE 7D
in EXAMPLE 7E. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.84 (bs, 1H), 8.04 (d,
1H), 7.87 (d, 1H), 7.80 (d, 1H), 7.74 (d, 1H), 7.65-7.52 (m, 5H), 7.51-7.32 (m, 5H), 6.97 (d,
1H), 5.74 (s, 2H), 4.96 (s, 2H), 3.88 (t, 2H), 3.64 (m, 4H), 3.26 (m, 4H), 3.00 (t, 2H).
EXAMPLE 73
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(4,4-
difluorocyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 73A
(4,4-difluorocyclohexyl)methanol
To a solution of ethyl 4,4-difluorocyclohexanecarboxylate (1.000 g) in diethyl ether
(5 mL) was added lithium aluminum hydride (1.0M in tetrahydrofuran) (6.24 mL) at 0°C.
The reaction was allowed to warm to room temperature and was stirred for 2 hours. The
reaction was cooled to 0°C and quenched with water (0.24 mL). 15% Aqueous NaOH (0.24
mL) was added followed by more water (0.72 mL). The reaction was stirred for 1 hour, and
magnesium sulfate was added. The mixture was filtered and concentrated to provide the title
compound.
EXAMPLE 73B
1-((4,4-difluorocyclohexyl)methyl)-1H-pyrazole
The title nd was prepared by tuting E 73A for (3-
(dimethylamino)phenyl)methanol and 1H-pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 73C
4-bromo((4,4-difluorocyclohexyl)methyl)methyl-1H-pyrazole
A solution of EXAMPLE 73B (0.795 g) in tetrahydrofuran (15 mL) was cooled to -
40°C. n-BuLi (1.6 M in hexanes, 2.98 mL) was added and the reaction was d for 1 hour,
then CH3I (0.298 mL) was added and the reaction warmed to 0°C. The on was diluted
with ethyl acetate (25 mL) and washed with water (25 mL) and brine (25 mL). The combined
organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was
dissolved in N,N-dimethylformamide (10 mL) and N-bromosuccinimide(0.777 g) was added.
After 1 hour, the reaction was diluted with ethyl acetate (75 mL), washed with water (50 mL)
and brine (50 mL), dried over magnesium sulfate, filtered and concentrated. Silica gel
chromatography eluting with a gradient of s/ethyl acetate provided the title compound.
EXAMPLE 73D
1-((4,4-difluorocyclohexyl)methyl)methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-
1H-pyrazole
The title compound was prepared by substituting EXAMPLE 73C for EXAMPLE
84C in EXAMPLE 84D.
EXAMPLE 73E
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((4,4-
difluorocyclohexyl)methyl)methyl-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 73D for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 73F
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(4,4-
difluorocyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 73E for E 8B
in E 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.86 (s, 2H), 8.04 (d,
1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.56 -7.40 (m, 3H), 7.36 (ddd, 2H), 7.28 (s, 1H), 6.95 (d,
1H), 4.95 (s, 2H), 4.09 -3.81 (m, 4H), 3.02 (d, 2H), 2.11 (s, 3H), 1.79 (m, 7H), 1.25 (d, 2H).
EXAMPLE 74
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(trifluoromethyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 74A
(1-(trifluoromethyl)cyclohexyl)methanol
The title compound was prepared by substituting 1-
trifluoromethylcyclohexanecarboxylic acid for 1-phenylcyclohexanecarboxylic acid in
E 67A.
EXAMPLE 74B
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)((1-(trifluoromethyl)cyclohexyl)methyl)-
1H-pyrazole
The title nd was prepared by substituting EXAMPLE 74A for (3-
(dimethylamino)phenyl)methanol in EXAMPLE 34A.
EXAMPLE 74C
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((1-
(trifluoromethyl)cyclohexyl)methyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 74B for 1-benzyl
,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 74D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(trifluoromethyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 74C for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.87 (s, 2H), 8.04 (d,
1H), 7.80 (d, 1H), 7.69 -7.73 (m, 2H), 7.57 -7.63 (m, 2H), 7.45 -7.51 (m, 1H), 7.41 -7.44
(m, 1H), 7.36 (t, 2H), 6.94 (d, 1H), 4.95 (s, 2H), 4.42 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H), 1.46 -
1.73 (m, 9H), 1.17 -1.32 (m, 1H).
EXAMPLE 75
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(diphenylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 75A
1-benzhydrylbromo-1H-pyrazole
A solution of 4-bromo-1H-pyrazole (0.294 g), (bromomethylene)dibenzene (0.494 g)
and ylamine (0.418 mL) in tetrahydrofuran (5 mL) was d at 60 °C for 24 hours.
The reaction mixture was concentrated and ed by chromatography on silica gel using 0-
20% ethyl acetate/hexanes as eluent to provide the title compound.
EXAMPLE 75B
tert-butyl 3-(1-benzhydryl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4-
dihydroisoquinolin-2(1H)-yl)picolinate
A suspension of EXAMPLE 30A (100 mg), EXAMPLE 75A (77 mg),
tris(dibenzylideneacetone)dipalladium(0) (7.47 mg), 1,3,5,7-tetramethylphenyl-2,4,8-
trioxaphosphaadamantane (7.16 mg) and potassium phosphate (104 mg) in tetrahydrofuran
(1.5 mL) and water (0.500 mL) was heated under microwave conditions (Biotage) at 80 °C
for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the organic layer
was separated, dried and purified by chromatography on silica gel using 10-60% ethyl
acetate/hexanes as eluent to provide the title compound.
EXAMPLE 75C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(diphenylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
A suspension of EXAMPLE 75B (30 mg) and lithium hydroxide (2 mg) in
ydrofuran and methanol (2:1, 1 mL) was heated at 60°C for 16 hours. The reaction
mixture was quenched with HCl (0.2 mL, 1M), concentrated and purified by chromatography
on silica gel using 0-5% methanol/dichloromethane as eluent to provide the title nd.
1H NMR (300 MHz, dimethylsulfoxide-d
6) G ppm 13.14 (s, 1H), 12.87 (s, 1H), 8.04 (d, 1H),
7.82 (s, 1H), 7.79 (d, 1H), 7.73 (d, 1H), 7.66 (s, 1H), 7.61 (d, 1H), 7.44 -7.51 (m, 1H), 7.40 -
7.44 (m, 1H), 7.29 -7.40 (m, 5H), 7.19 (d, 4H), 6.93 (t, 2H), 4.94 (s, 2H), 3.94 (s, 1H), 3.86
(t, 2H), 2.99 (t, 1H).
E 76
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(morpholin-
4-yl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 76A
(4-bromo-1H-pyrazolyl)methyl)phenyl)morpholine
The title nd was prepared by substituting o-1H-pyrazole for 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole and (2-morpholinophenyl)methanol for (3-
(dimethylamino)phenyl)methanol in EXAMPLE 34A.
EXAMPLE 76B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(2-
morpholinobenzyl)-1H-pyrazolyl)picolinate
The title compound was ed by substituting EXAMPLE 76A for EXAMPLE
77D in EXAMPLE 77E.
EXAMPLE 76C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(morpholin-
4-yl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
The title nd was prepared by substituting EXAMPLE 76B for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.84 (s, 1H), 8.04 (d,
1H), 7.89 (s, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.61 (d, 1H), 7.57 (s, 1H), 7.40 -7.51 (m, 2H),
7.36 (t,2H), 7.24 -7.32 (m, 1H), 7.18 -7.23 (m, 1H), 7.02 -7.10 (m, 1H), 6.94 (d, 1H), 6.86 -
6.92 (m, 1H), 5.41 (s, 2H), 4.94 (s, 2H), 3.87 (t, 2H), 3.72 -3.78 (m, 4H), 3.00 (t, 2H), 2.78 -
2.86 (m, 4H).
EXAMPLE 77
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-(morpholin-
4-yl)phenylpropyl]-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 77A
-dimethoxyphenylpropyl)-1H-pyrazole
To a solution of 1-benzyl-1H-pyrazole (0.653 g) in tetrahydrofuran (5 mL) cooled to -
78oC was dropwise added 1.6M n-butyllithium (2.84 mL). The reaction mixture was stirred
for 60 minutes, and 2-chloro-1,1-dimethoxyethane (0.517 mL) was added, and stirring
continued for 3 hours. The reaction e was allowed to slowly warm up to room
temperature, and was quenched with water, extracted with ether, dried over , filtered,
and concentrated. The product was purified by chromatography on silica gel using 0-20%
ethyl acetate/hexanes as the eluent to e the title compound.
EXAMPLE 77B
4-bromo(3,3-dimethoxyphenylpropyl)-1H-pyrazole
The title compound was ed by substituting EXAMPLE 77A for EXAMPLE
63B in EXAMPLE 63C.
EXAMPLE 77C
3-(4-bromo-1H-pyrazolyl)phenylpropanal
A solution of EXAMPLE 77B (0.34 g) and hydrochloric acid (2 mL) in
tetrahydrofuran (3.5 mL) was stirred at room temperature for 16 hours. The reaction mixture
was concentrated, redissolved in dichloromethane, dried over magnesium sulfate, ed, and
used in the next step without cation.
EXAMPLE 77D
4-(3-(4-bromo-1H-pyrazolyl)phenylpropyl)morpholine
A suspension of EXAMPLE 77C (150 mg), morpholine (0.117 mL), acetic acid
(0.062 mL) and solid-supported MP-CNBH3 (Argonaut Technologies, 885 mg, 2.63 mmol/g)
in dichloromethane (4 mL) and methanol (2 mL) was shaken at room temperature for 18
hours. The reaction mixture was filtered, concentrated and purified by RP HPLC (30 - 100%
CH3CN/water/0.1% TFA) to provide the title compound.
EXAMPLE 77E
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(3-
morpholinophenylpropyl)-1H-pyrazolyl)picolinate
A suspension of EXAMPLE 30A (100 mg), EXAMPLE 77D (50 mg),
tris(dibenzylideneacetone)dipalladium(0) (14 mg), 1,3,5,7-tetramethylphenyl-2,4,8-trioxa-
6-phosphaadamantane (24 mg) and potassium phosphate (104 mg) in tetrahydrofuran (3 mL)
and water (1.5 mL) was heated under microwave conditions (Biotage) at 140°C for 5 minutes.
The reaction mixture was diluted with ethyl acetate, separated, and purified by
chromatography on silica gel using 10-60% ethyl acetate/hexanes as eluent to provide the title
compound.
E 77F
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-(morpholin-
4-yl)phenylpropyl]-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 77E for E 8B
in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (s, 1H), 9.65 (s,
1H), 8.04 (d, 1H), 7.97 (s, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.67 (s, 1H), 7.61 (d, 1H), 7.45 -
7.52 (m, 1H), 7.42 (t, 1H), 7.29 -7.39 (m, 7H), 6.95 (d, 1H), 5.57 (dd, 1H), 4.95 (s, 2H), 3.96
(d, 4H), 3.82 -3.90 (m, 2H), 3.60 (t, 2H), 3.46 (d, 2H), 3.04 - 3.17 (m, 4H), 3.00 (t, 2H), 2.76
-2.93 (m, 2H).
E 78
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(tertbutoxycarbonyl
)piperidinyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 78A
tert-butyl 4-((4-bromo-1H-pyrazolyl)methyl)piperidinecarboxylate
The title nd was prepared by substituting 4-bromo-1H-pyrazole for 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole and tert-butyl 4-
(hydroxymethyl)piperidinecarboxylate for (3-(dimethylamino)phenyl)methanol in
EXAMPLE 34A.
EXAMPLE 78B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((1-
butoxycarbonyl)piperidinyl)methyl)-1H-pyrazolyl)picolinate
The title compound was ed by substituting EXAMPLE 78A for EXAMPLE
77D in EXAMPLE 77E.
EXAMPLE 78C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(tertbutoxycarbonyl
)piperidinyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 78B for EXAMPLE
75B in E 75C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.58 -13.32 (m,
1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.76 (s, 1H), 7.69 (d, 1H), 7.61 (d, 1H), 7.54 (s, 1H), 7.45 -
7.51 (m, 1H), 7.39 -7.44 (m, 1H), 7.36 (t, 2H), 6.93 (d, 1H), 4.94 (s, 2H), 3.80 -4.04 (m, 4H),
3.00 (t, 2H), 2.69 (d, 2H), 1.86 -2.02 (m, 1H), 1.45 (d, 2H), 1.37 (s, 9H), 0.93 -1.14 (m, 2H).
EXAMPLE 79
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-methyl{2-
[2-(morpholinyl)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 79A
1-(2-(benzyloxy)benzyl)iodomethyl-1H-pyrazole
The title compound was prepared by substituting 3-methyliodopyrazole for 4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole and 1-(benzyloxy)
(bromomethyl)benzene for EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 79B
2-((4-iodomethyl-1H-pyrazolyl)methyl)phenol
In a 20 mL round-bottomed flask, E 79A (0.65 g) was added to
dichloromethane (5 mL) to give a on. The on was cooled to 0ºC, and
tribromoborane (1.7 mL, 1M in hexane) was added slowly. After stirring at room temperature
for 4 hours, methanol (10 mL) was added slowly. The solvent was removed, and the residue
taken up into dichloromethane and purified by flash chromatography (Varian, Superflash
SF25-40g column), eluting with 0-30% ethyl acetate/hexane to e the title compound.
EXAMPLE 79C
EXAMPLE 79B (0.05 g), 2-(morpholino)ethanol (0.03 g), di-tert-butyl
azodicarboxylate (0.06 g) and triphenylphosphine (0.1 g) were stirred at room temperature
overnight. The crude product was purified by flash chromatography (Varian, Superflash
SF25-40g ), g with 0-10% methanol in dichloromethane to provide the title
compound.
EXAMPLE 79D
Tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(5-
methyl(2-(2-morpholinoethoxy)benzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 79C for EXAMPLE
77D in EXAMPLE 77E.
EXAMPLE 79E
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-methyl{2-
[2-(morpholinyl)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 79D for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (300 MHz, ylsulfoxide-d 6) G ppm 12.84 (s, 1H), 9.84 (s,
1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.57 (m, 2H), 7.36 (m, 6H), 7.08 (d, 1H), 6.94 (m, 2H), 6.66
(d, 1H), 5.32 (s, 2H), 4.96 (s, 2H), 4.39 (m, 2H), 4.01 (m, 2H), 3.89 (t, 2H), 3.25 (m, 2H),
3.01 (t, 2H), 2.07 (d, 3H).
EXAMPLE 80
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(dimethylamino)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 80A
(2-(dimethylamino)phenyl)methanol
In a 250 mL round-bottomed flask, (3-(dimethylamino)phenyl)methanol (1 g) and
paraformaldehyde (2.5 g) were added to acetic acid (150 mL) to give a suspension. Sodium
cyanoborohydride (2.6 g) was added slowly. The mixture was stirred at room temperature
overnight. After concentration of the solvent, water and ethyl acetate (1:1, 100 mL) were
added. After separation, the aqueous layer was extracted by ethyl acetate (2x 20 mL). The
combined organic layers were washed with water (3x 50 mL), saturated aqueous NaHCO3 (2x
mL), and dried over Na2SO4. After filtration and concentration, the residue was taken up
into CH2Cl2 and the product was purified by flash chromatography (Varian, Superflash SF40-
80g ), eluting with 0-20% ol/dichloromethane, to provide the title nd.
EXAMPLE 80B
iodo-1H-pyrazolyl)methyl)-N,N-dimethylaniline
The title compound was prepared by substituting 4-iodopyrazole for 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole and EXAMPLE 80A for EXAMPLE 4A in
EXAMPLE 4B.
EXAMPLE 80C
Tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(2-
(dimethylamino)benzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 80B for EXAMPLE
77D in EXAMPLE 77E.
EXAMPLE 80D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-
(dimethylamino)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 80C for EXAMPLE 1E
in E 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.84 (s, 1H), 8.04 (d,
1H), 7.89 (s, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.61 (m, 2H), 7.37 (m, 6H), 7.03 (m, 1H), 6.94
(d, 1H), 6.85 (d, 1H), 5.42 (s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H), 2.71 (s, 6H).
EXAMPLE 81
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-methyl{2-
[3-(morpholinyl)propoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 81A
4-(3-(2-((4-iodomethyl-1H-pyrazolyl)methyl)phenoxy)propyl)morpholine
The title compound was prepared by tuting 3-morpholinopropanol for 2-
morpholinoethanol in EXAMPLE 79C.
EXAMPLE 81B
Tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(5-
methyl(2-(3-morpholinopropoxy)benzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by tuting EXAMPLE 81A for EXAMPLE
77D in EXAMPLE 77E.
EXAMPLE 81C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-methyl{2-
[3-(morpholinyl)propoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 81B for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (300 MHz, ylsulfoxide-d 6) G ppm 12.84 (s, 1H), 8.04 (d,
1H), 7.79 (d, 1H), 7.44 (m, 9H), 6.95 (m, 3H), 6.60 (d, 1H), 5.29 (s, 2H), 4.96 (s, 2H), 4.12(t,
2H), 3.95 (m, 4H), 3.57 (m, 4H), 3.36 (m, 2H), 3.07 (m, 4H), 2.17 (m, 2H), 2.07 (s, 3H).
EXAMPLE 82
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-methyl[(1-
methylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 82A
(1-methylcyclohexyl)methanol
The title compound was prepared by substituting 1-methylcyclohexanecarboxylic
acid for ethyl 4,4-difluorocyclohexanecarboxylate in EXAMPLE 73A.
EXAMPLE 82B
methylcyclohexyl)methyl)-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 82A for (3-
(dimethylamino)phenyl)methanol and 1H-pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole in E 34A.
EXAMPLE 82C
4-bromomethyl((1-methylcyclohexyl)methyl)-1H-pyrazole
The title nd was prepared by substituting EXAMPLE 82B for EXAMPLE
63A in EXAMPLE 63B and then substituting that product for EXAMPLE 63B in EXAMPLE
63C.
EXAMPLE 82D
-methyl((1-methylcyclohexyl)methyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-
1H-pyrazole
The title compound was prepared by substituting EXAMPLE 82C for EXAMPLE
63C in EXAMPLE 63D.
EXAMPLE 82E
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)
hyl((1-methylcyclohexyl)methyl)-1H-pyrazolyl)picolinate
A mixture of EXAMPLE 1D (0.240 g), EXAMPLE 82D (0.135 g), 1,3,5,7-
tetramethylphenyl-2,4,8-trioxaphosphaadamantane (0.012 g), potassium phosphate
(0.315 g) and tris(dibenzylideneacetone)dipalladium(0) (0.022 g) were added to N,N-
ylformamide (0.6 mL), dioxane (0.4 mL) and water (0.2 mL). The reaction was
degassed with nitrogen, sealed and heated to 110°C. After 3 hours the reaction was cooled,
diluted with ethyl acetate (50 mL) and washed with water (30 mL) and brine (30 mL). The
reaction was dried over ium sulfate, filtered, and concentrated. Silica gel
chromatography eluting with a nt of 5% to 45% ethyl acetate/hexanes over 30 minutes
provided the title nd.
EXAMPLE 82F
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-methyl[(1-
methylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 82E for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR (300 MHz, CDCl 3) δ ppm 7.85(dt, 1H), 7.68 -7.62 (m, 1H),
7.59 (dd, 1H), 7.53 (d, 1H), 7.45 -7.30 (m, 5H), 7.01 (d, 1H), 5.17 (s, 2H), 3.89 (m, 4H), 3.12
(s, 2H), 2.09 (s, 3H), 1.49 (m, 10H), 0.96 (s, 3H).
EXAMPLE 83
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[2-(4-
chlorophenyl)-4,4-dimethylcyclohexenyl]methyl}-1H-pyrazolyl)pyridine
carboxylic acid
E 83A
methyl 4,4-dimethyl(trifluoromethylsulfonyloxy)cyclohexenecarboxylate
To a suspension of hexane washed NaH (17 g) in dichloromethane (700 mL) was
added 5,5-dimethylmethoxycarbonylcyclohexanone (38.5 g) dropwise at 0oC. After
stirring for 30 minutes, the mixture was cooled to –78oC and trifluoroacetic anhydride (40
mL) was added. The reaction mixture was warmed to room temperature and stirred for 24
hours. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to
provide the title compound.
EXAMPLE 83B
methyl 2-(4-chlorophenyl)-4,4-dimethylcyclohexenecarboxylate
EXAMPLE 83A (62.15 g), 4-chlorophenylboronic acid (32.24 g), CsF (64 g) and
tetrakis(triphenylphosphine)palladium(0) (2 g) in 2:1 dimethoxyethane /methanol(600 mL)
were heated to 700C for 24 hours. The mixture was concentrated. Diethyl ether (4x 200 mL)
was added and the mixture was filtered. The ed ether solution was concentrated to
provide the title compound.
EXAMPLE 83C
(2-(4-chlorophenyl)-4,4-dimethylcyclohexenyl)methanol
To a e of LiBH4 (13 g), EXAMPLE 83B (53.8 g) and ether (400 mL), was
added methanol (25 mL) slowly by syringe. The mixture was stirred at room temperature for
24 hours. The reaction was quenched with 1N HCl with ice-cooling. The mixture was diluted
with water and extracted with ether (3x 100 mL). The combined extracts were dried
(Na2SO4), filtered, and concentrated. The crude product was purified on silica gel with 0-30%
ethyl acetate/hexanes.
EXAMPLE 83D
1-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohexenylmethyl](4,4,5,5-tetramethyl-
[1,3,2]dioxaborolanyl)-1H-pyrazole
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (340 mg) and
EXAMPLE 83C (400 mg) were dissolved in toluene (12 mL).
ethylenetributylphosphorane (462 mg) was added, and the solution was mixed at
room temperature for 16 hours. The solution was concentrated and purified on silica gel
using 10% ethyl acetate in hexanes.
EXAMPLE 83E
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[2-(4-
chlorophenyl)-4,4-dimethylcyclohexenyl]methyl}-1H-pyrazolyl)pyridine
carboxylic acid utyl ester
The title compound was ed by substituting EXAMPLE 83D for EXAMPLE
58A in EXAMPLE 58B.
EXAMPLE 83F
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[2-(4-
chlorophenyl)-4,4-dimethylcyclohexenyl]methyl}-1H-pyrazolyl)pyridine
ylic acid
The title nd was prepared by substituting EXAMPLE 83E for EXAMPLE 7D
in EXAMPLE 7E. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (bs, 1H), 8.05 (d,
1H), 7.80 (d, 1H), 7.71 (d, 1H), 7.61 (d, 1H), 7.51-7.31 (m, 10H), 6.95 (d, 1H), 4.95 (s, 2H),
4.53 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H), 2.05 (bs, 2H), 1.88 (t, 2H), 1.36 (t, 2H), 0.92 (s, 6H).
EXAMPLE 84
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)ethyl-1H-pyrazolyl]pyridinecarboxylic acid
E 84A
lohexylmethyl)-1H-pyrazole
The title compound was prepared by substituting (bromomethyl)cyclohexane for
(bromomethyl)cyclopentane in EXAMPLE 63A.
EXAMPLE 84B
1-(cyclohexylmethyl)ethyl-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 84A for EXAMPLE
63A and ethyl iodide for iodomethane in EXAMPLE 63B.
EXAMPLE 84C
4-bromo(cyclohexylmethyl)ethyl-1H-pyrazole
The title nd was prepared by substituting EXAMPLE 84B for EXAMPLE
63B in EXAMPLE 63C.
EXAMPLE 84D
1-(cyclohexylmethyl)ethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
EXAMPLE 84C (225 mg) was placed into a flask and degassed with N2.
Tetrahydrofuran (3 mL) and toluene (2 mL) were added and the solution was cooled to -78oC.
Triisopropyl borate (0.23 mL) was added, followed by dropwise addition of llithium
(2.3 M in hexanes, 0.6 mL) over 5 minutes. The mixture was stirred for 10 minutes at -78oC
and then a degassed on of pinacol (135 mg) in tetrahydrofuran (1 mL) was added over 2
minutes. After stirring for 10 minutes at -78oC, the reaction was warmed to room temperature
and stirred for 1 hour. Water (0.07 mL) was then added and the mixture was stirred for 2
hours. The crude reaction mixture was concentrated to dryness to provide the title compound.
EXAMPLE 84E
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
(cyclohexylmethyl)ethyl-1H-pyrazolyl)picolinate
The title nd was prepared by substituting EXAMPLE 84D for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 84F
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(cyclohexylmethyl)ethyl-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 84E for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.87 (s, 1H), 12.61 -
12.90 (br s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.41 -7.51 (m, 3H),
7.32-7.40 (m, 2H), 7.21 (s, 1H), 6.93 (d, 1H), 4.95 (s, 2H), 3.88 (t, 2H), 3.83 (d , 2H), 3.01
(t, 2H), 2.54 (q, 2H), 1.76 - 1.93 (m, 1H), 1.58 - 1.72 (m, 3H), 1.52 (d, 2H), 1.08 - 1.25 (m,
3H), 0.96 (t, 3H), 0.89 - 1.05 (m, 2H).
E 85
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[(1R,2R,5R)-
6,6-dimethylbicyclo[3.1.1]heptyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid
EXAMPLE 85A
1-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptanyl)methyl)-1H-pyrazole
The title compound was prepared by substituting ((1R,2R,5R)-6,6-
ylbicyclo[3.1.1]heptanyl)methanol for (3-(dimethylamino)phenyl)methanol and
pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 85B
1-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptanyl)methyl)methyl-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 85A for E
63A in EXAMPLE 63B.
EXAMPLE 85C
4-bromo(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptanyl)methyl)methyl-1H-
pyrazole
The title compound was prepared by substituting EXAMPLE 85B for EXAMPLE
63B in EXAMPLE 63C.
EXAMPLE 85D
1-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptanyl)methyl)methyl(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 85C for EXAMPLE
84C in EXAMPLE 84D.
EXAMPLE 85E
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptanyl)methyl)methyl-1H-pyrazol
yl)picolinate
The title compound was ed by substituting EXAMPLE 85D for EXAMPLE
82D in EXAMPLE 82E.
EXAMPLE 85F
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[(1R,2R,5R)-
6,6-dimethylbicyclo[3.1.1]heptyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid
The title compound was ed by substituting EXAMPLE 85E for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 1H), 12.77 (br
s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.47 (m, 3H), 7.35 (m, 2H), 7.25 (s, 1H), 6.94
(d, 1H), 4.95 (s, 2H), 3.89 (d, 2H), 3.84 (d, 2H), 3.01 (t, 2H), 2.49 (m, 1H), 2.08 (s, 3H), 2.04
(m, 1H), 1.84 (m, 1H), 1.73 (m, 2H), 1.60 (t, 1H), 1.51 (m, 1H), 1.41 (d, 1H), 1.35 (m, 1H),
1.15 (s, 3H), 0.78 (s, 3H).
E 86
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[(1S,2R,5S)-
6,6-dimethylbicyclo[3.1.1]heptyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid
EXAMPLE 86A
1-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptanyl)methyl)-1H-pyrazole
The title compound was prepared by substituting ((1S,2R,5S)-6,6-
dimethylbicyclo[3.1.1]heptanyl)methanol for (3-(dimethylamino)phenyl)methanol and
pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 86B
1-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptanyl)methyl)methyl-1H-pyrazole
The title compound was ed by substituting E 86A for EXAMPLE
63A in EXAMPLE 63B.
EXAMPLE 86C
4-bromo(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptanyl)methyl)methyl-1H-
pyrazole
The title compound was prepared by substituting E 86B for EXAMPLE
63B in EXAMPLE 63C.
EXAMPLE 86D
1-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptanyl)methyl)methyl(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 86C for EXAMPLE
84C in E 84D.
EXAMPLE 86E
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptanyl)methyl)methyl-1H-pyrazol
yl)picolinate
A reaction vessel was charged with EXAMPLE 1D (200 mg), EXAMPLE 86D (183
mg), tris(dibenzylideneacetone)dipalladium(0) (18.30 mg), 1,3,5,7-tetramethylphenyl-
2,4,8-trioxaphosphaadamantane (10.34 mg) and K3PO4 (263 mg) and the vessel was sealed
with a septum and purged with N2. A sparged mixture of dioxane (1 mL) and water (1.000
mL) was added to the degassed reagents and the mixture was heated to 110oC for 5 hours.
The reaction mixture was partitioned n water (15 mL) and ethyl acetate (3x 20 mL).
The combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated.
The title compound was purified by flash chromatography (gradient from 0 to 50% ethyl
acetate/ s).
EXAMPLE 86F
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[(1S,2R,5S)-
6,6-dimethylbicyclo[3.1.1]heptyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid
The title compound was prepared by substituting EXAMPLE 85E for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d6) G ppm 12.86 (s, 1H), 12.56 -
13.01 (br s, 1H), 8.04 (d , 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.40 -7.52 (m, 3H), 7.30 -7.40 (m,
2H), 7.26 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.91 -4.09 (m, 2H), 3.89 (t, 2H), 3.01 (t, 2H),
2.51-2.60 (m, 1H), 2.21 -2.36 (m, 1H), 2.11 (s, 3H), 1.68 -1.98 (m, 5H), 1.54 (s, 1H), 1.17
(s, 3H), 1.11 (s, 3H), 0.85 (d, 1H).
EXAMPLE 87
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methylpropyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 87A
(1-isobutylcyclohexyl)methanol
To a solution of lithium diisopropylamide (2.0 M, 7.74 mL) at -78°C was added
methyl cyclohexanecarboxylate (2.0 g) dropwise as a solution in tetrahydrofuran (20 mL).
After stirring for 30 minutes, 1-iodomethylpropane (1.956 mL) was added dropwise as a
solution in tetrahydrofuran (1 mL). The reaction was allowed to warm to room temperature
and d overnight. The reaction was quenched with 1N HCl (25 mL) and diluted with
water (25 mL) and extracted into diethyl ether (50 mL). The ether layer was washed with
brine (30 mL), dried over magnesium sulfate, filtered and concentrated. The residue was
dissolved in diethyl ether (25 mL) and lithium um e (1.0M in tetrahydrofuran,
16.88 mL) was added dropwise. After stirring overnight, the reaction was ed with
water (0.65 mL), 15% aqueous NaOH (0.65 mL), more water (1.95 mL), then magnesium
sulfate was added and the on filtered and concentrated. The residue was loaded onto
silica gel and eluted using a gradient of 3% to 20% ethyl acetate/hexanes to provide the title
compound.
E 87B
1-((1-isobutylcyclohexyl)methyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazole
The title compound was prepared by tuting EXAMPLE 87A for (3-
(dimethylamino)phenyl)methanol in EXAMPLE 34A.
E 87C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methylpropyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 1D (0.150 g), EXAMPLE 87B (0.119 g),
bis(triphenylphosphine)palladium(II) dichloride (0.019 g) and cesium carbonate (0.259 g)
were stirred together in N,N-dimethylformamide (0.45 mL), dioxane (0.3 mL) and water
(0.15 mL) in a microwave reactor at 120°C for 15 minutes. The reaction was loaded onto
silica gel and eluted using a gradient of 5% to 50%. The corresponding ester was collected,
treated with dichloromethane (0.5 mL) and TFA (0.5 mL) and stirred overnight. The reaction
was concentrated, loaded onto silica gel and eluted using a gradient of 0.25% to 2.5%
methanol/dichloromethane to e the title compound. 1H NMR (300 MHz,
dimethylsulfoxide-d6) G ppm 13.19 -12.64 (m, 2H), 8.08 -8.00 (m, 1H), 7.82 -7.76 (m, 1H),
7.74-7.67 (m, 2H), 7.66 -7.57 (m, 1H), 7.54 (s, 1H), 7.51 -7.45 (m, 1H), 7.37 (d, 3H), 6.94
(d, 1H), 4.94 (s, 2H), 4.03 (s, 2H), 3.87 (s, 2H), 3.00 (s, 2H), 1.90 -1.68 (m, 1H), 1.28 (m,
10H), 1.19 -1.09 (m, 2H), 0.91 (d, 6H).
EXAMPLE 88
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid
E 88A
methyl 1-(2-methoxyethyl)cyclohexanecarboxylate
To a cooled ) solution of lithium diisopropylamide (2.0 M, 20 mL) in
tetrahydrofuran (20 mL) was added methyl cyclohexanecarboxylate (5.0 g) in tetrahydrofuran
(30 mL). The mixture was stirred at -78oC for 30 minutes and a solution of 1-bromo
yethane (5.86 g) in tetrahydrofuran (10 mL) was added. The mixture was d
overnight and the temperature was allowed to warm up to room temperature. The mixture
was quenched with aqueous NH4Cl and extracted with ethyl acetate (200 mL) and washed
with water (3x), brine and dried over Na2SO4. Filtration and ation of solvent gave
crude product which was used in the next reaction without further purification.
EXAMPLE 88B
(1-(2-methoxyethyl)cyclohexyl)methanol
A solution of EXAMPLE 88A (7.0 g) in diethyl ether (30 mL) was added dropwise to
a sion of LiAlH4 (1.32 g) in diethyl ether (50 mL). Once the addition was finished, the
mixture was refluxed for 90 minutes. Then cooled to 0oC and 2N NaOH (50 mL) was added
slowly. Once a semi-solid appeared at the bottom of the flask, ethyl acetate (300 mL) was
added and the mixture was stirred vigorously for 30 minutes. The top clear layer was
decanted and more ethyl e (200 mL) was added to the mixture and stirred for another 15
minutes. The top organic layer was ed and combined with the previous one. The
combined organic layers were washed with 2N aqueous NaOH, water, brine and dried over
Na2SO4. Filtration and evaporation of solvent gave the title compound.
E 88C
(2-methoxyethyl)cyclohexyl)methyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-
1H-pyrazole
The title compound was prepared by tuting EXAMPLE 88B for (3-
(dimethylamino)phenyl)methanol in EXAMPLE 34A.
EXAMPLE 88D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid
To a mixture of EXAMPLE 1D (162 mg) and EXAMPLE 88C (100 mg) in dioxane
(9 mL) was added tetrakis(triphenylphosphine)palladium(0) (17 mg) and saturated aqueous
NaHCO3 (3 mL). The mixture was purged with argon and stirred at 120°C in a Biotage
Initiator microwave reactor for 30 minutes. The mixture was diluted with ethyl acetate (200
mL) and washed with water, brine and dried over Na2SO4. Filtration and ation of
solvent gave crude product which was loaded on a silica gel dge and eluted with 20%
ethyl acetate in dichloromethane to give product which was dissolved in dichloromethane (3
mL) and TFA (3 mL) and stirred overnight. After evaporation of solvent, the residue was
loaded on a silica gel cartridge and eluted with 5% methanol in dichloromethane to give the
pure acid. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.84 (s, 1H), 8.04 (d, 1H), 7.79
(d, 1H), 7.72 (s, 2H), 7.68 (s, 1H), 7.61 (d, 2H), 7.54 (m, 2H), 7.43 (m, 6H), 6.94 (d, 2H),
4.94 (s, 3H), 4.01 (s, 2H), 3.87 (t, 2H), 3.39 (t, 2H), 3.21 (m, 2H), 3.00 (t, 2H), 1.38 (m, 12H).
EXAMPLE 89
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(2-
methoxyethoxy)benzyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 89A
4-iodo(2-(2-methoxyethoxy)benzyl)methyl-1H-pyrazole
The title compound was prepared by tuting 2-methoxyethanol for 2-
morpholinoethanol in EXAMPLE 79C.
EXAMPLE 89B
Tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(2-(2-
yethoxy)benzyl)methyl-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 89A for EXAMPLE
77D in E 77E.
EXAMPLE 89C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(2-
methoxyethoxy)benzyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting E 89B for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (s, 1H), 8.04 (d,
1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.48 (m, 3H), 7.35 (m, 3H), 7.24 (m, 1H), 7.03 (d, 1H), 6.96
(d, 1H), 6.87 (t, 1H), 6.69 (t, 1H), 5.22 (s, 2H), 4.96 (s, 2H), 4.15 (m, 2H), 3.89 (t, 2H), 3.69
(m, 2H), 3.32 (s, 3H), 3.02 (t, 2H), 2.10 (s, 3H).
EXAMPLE 90
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 90A
1-((1-(2-methoxyethyl)cyclohexyl)methyl)-1H-pyrazole
The title compound was ed by substituting EXAMPLE 88B for (3-
(dimethylamino)phenyl)methanol and pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 90B
1-((1-(2-methoxyethyl)cyclohexyl)methyl)methyl-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 90A for EXAMPLE
63A in EXAMPLE 63B.
EXAMPLE 90C
4-iodo((1-(2-methoxyethyl)cyclohexyl)methyl)methyl-1H-pyrazole
The title nd was prepared by substituting EXAMPLE 90B for EXAMPLE
65E in EXAMPLE 65F.
EXAMPLE 90D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by first substituting E 90C for
EXAMPLE 77D in EXAMPLE 77E, and then substituting the product from that reaction for
EXAMPLE 8B in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.85
(s, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.40 (m, 8 H), 7.29 (s, 1H), 6.96 (d, 2H), 4.95 (s, 2H), 3.88
(m, 4H), 3.37 (t, 2H), 3.21 (s, 3H), 3.00 (t, 2H), 2.11 (s, 3H), 1.59 (t, 2H), 1.34 (m, 10 H).
E 91
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1R,2R,4R)-
bicyclo[2.2.1]heptenylmethyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 91A
1-((1R,2R,4R)-bicyclo[2.2.1]heptenylmethyl)-1H-pyrazole
The title compound was prepared by substituting (1R,2R,4R)-bicyclo[2.2.1]hept
enylmethanol for (3-(dimethylamino)phenyl)methanol and pyrazole for 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 91B
,2R,4R)-bicyclo[2.2.1]heptenylmethyl)methyl-1H-pyrazole
The title compound was ed by substituting EXAMPLE 91A for EXAMPLE
63A in EXAMPLE 63B.
EXAMPLE 91C
1-((1R,2R,4R)-bicyclo[2.2.1]heptenylmethyl)bromomethyl-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 91B for EXAMPLE
63B in EXAMPLE 63C.
E 91D
1-((1R,2R,4R)-bicyclo[2.2.1]heptenylmethyl)methyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 91C for EXAMPLE
84C in EXAMPLE 84D.
EXAMPLE 91E
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
((1R,2R,4R)-bicyclo[2.2.1]heptenylmethyl)methyl-1H-pyrazolyl)picolinate
The title compound was ed by substituting EXAMPLE 91D for EXAMPLE
86D in EXAMPLE 86E.
EXAMPLE 91F
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1R,2R,4R)-
bicyclo[2.2.1]heptenylmethyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 91E for E 8B
in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.84 (s, 1H), 12.56 -
13.05 (br s, 1H), 7.79 (d, 1H) 8.04 (d, 1H), 7.61 (d, 1H), 7.50 (d, 1H), 7.40 -7.50 (m, 2H),
.40 (m, 2H), 7.27 (s, 1H), 6.95 (d, 1H), 6.25 (dd, 1H), 6.08 (dd, 1H), 4.95 (s, 2H), 3.89
(t, 2H), 3.76 (dd, 1H), 3.64 (dd, 1H), 3.01 (t, 2H), 2.79 (m, 1H), 2.63 (m, 1H), 2.54 -2.59 (m,
1H), 2.11 (s, 3H), 1.75 -1.85 (m, 1H), 1.33 (dd, 1H), 1.20 -1.26 (m, 1H), 0.59 -0.67 (m, 1H).
EXAMPLE 92
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,3-
dimethylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 92A
(3,3-dimethylcyclohexyl)methanol
To a suspension of (methoxymethyl)triphenylphosphonium chloride (3.26 g) in
tetrahydrofuran (20 mL) at 0°C was added n-butyllithium (2.5 M, 5.94 mL) dropwise. The
reaction was stirred for 15 minutes, then 3,3-dimethylcyclohexanone (1.000 g) as a solution in
tetrahydrofuran (3 mL) was added dropwise. After the addition, the reaction was allowed to
warm to room temperature and stir for 2 hours. The reaction was d with diethyl ether
(50 mL) and washed with 1N aqueous HCl (50 mL), brine (50 mL), dried over magnesium
sulfate, filtered and concentrated. Silica gel chromatography eluting with a nt of 1% to
% ethyl acetate/hexanes gave the vinyl ether. The material was dissolved in tetrahydrofuran
(25 mL) and added HCl (27.7 mL) and stirred overnight. The reaction was diluted with
diethyl ether (50 mL) and washed with brine (50 mL), dried over magnesium sulfate and
concentrated. The residue was dissolved in methanol (10 mL) and sodium borohydride
(0.090 g) was added and the mixture was stirred for 1 hours. The reaction was diluted with
diethyl ether (50 mL) and washed with 1M aqueous HCl (50 mL) and brine (50 mL). The
ed c layers dried over magnesium sulfate, filtered, and concentrated. Silica gel
chromatography eluting with a gradient of 5% to 30% ethyl acetate/hexanes provided the title
compound.
E 92B
1-((3,3-dimethylcyclohexyl)methyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazole
The title compound was prepared by substituting EXAMPLE 92A for (3-
(dimethylamino)phenyl)methanol in EXAMPLE 34A.
EXAMPLE 92C
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3,3-
dimethylcyclohexyl)methyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 92B for E
22A in EXAMPLE 22B.
EXAMPLE 92D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,3-
dimethylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 92C for EXAMPLE 8B
in EXAMPLE 8C. 1H NMR (300 MHz, ylsulfoxide-d 6) δ ppm 12.85 (s, 1H), 8.04 (d,
1H), 7.79 (d, 1H), 7.74 (d, 1H), 7.70 (d, 1H), 7.61 (d, 1H), 7.52 (d, 1H), 7.51 -7.45 (m, 1H),
7.44-7.32 (m, 3H), 6.94 (d, 1H), 4.94 (s, 2H), 3.92 -3.81 (m, 4H), 3.00 (t, 2H), 1.95 (s, 1H),
1.58-0.91 (m, 6H), 0.85 (m, 6H), 0.79 (d, 2H).
EXAMPLE 93
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-methoxy
propyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 93A
1-(3-methoxyphenylpropyl)-1H-pyrazole
The title compound was prepared by substituting 1-bromomethoxyethane for 2-
chloro-1,1-dimethoxyethane in EXAMPLE 77A.
EXAMPLE 93B
4-iodo(3-methoxyphenylpropyl)-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 93A for EXAMPLE
66B in EXAMPLE 66C.
EXAMPLE 93C
tert-butyl benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(3-
methoxyphenylpropyl)-1H-pyrazolyl)picolinate
The title compound was ed by substituting EXAMPLE 93B for EXAMPLE
77D in EXAMPLE 77E.
EXAMPLE 93D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-
methoxyphenylpropyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by tuting EXAMPLE 93C for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.84 (s, 1H), 8.04 (d,
1H), 7.98 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.61 (d, 1H), 7.58 (s, 1H), 7.47 (t, 1H), 7.39 -
7.44 (m, 1H), 7.25 -7.39 (m, 7H), 6.94 (d, 1H), 5.51 (dd, 1H), 4.94 (s, 2H), 3.86 (t, 2H), 3.09
-3.24 (m, 5H), 2.99 (t, 2H), 2.53-2.62 (m, 1H), 2.24 -2.38 (m, 1H).
EXAMPLE 94
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-methoxy
phenylbutyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 94A
1-(4-methoxyphenylbutyl)-1H-pyrazole
The title compound was ed by substituting 1-bromomethoxypropane for 2-
chloro-1,1-dimethoxyethane in E 77A.
EXAMPLE 94B
4-iodo(4-methoxyphenylbutyl)-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 94A for EXAMPLE
65E in EXAMPLE 65F.
EXAMPLE 94C
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(4-
methoxyphenylbutyl)-1H-pyrazolyl)picolinate
The title compound was prepared by tuting EXAMPLE 94B for EXAMPLE
77D in EXAMPLE 77E.
EXAMPLE 94D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-methoxy
phenylbutyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 94C for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (300 MHz, ylsulfoxide-d 6) G ppm 12.84 (s, 1H), 8.04 (d,
1H), 7.96 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.61 (d, 1H), 7.57 (s, 1H), 7.44 -7.52 (m, 1H),
7.40-7.44 (m, 1H), 7.21 -7.39 (m, 7H), 6.93 (d, 1H), 5.41 (dd, 1H), 4.94 (s, 2H), 3.86 (t,
2H), 3.31 (t, 2H), 3.18 (s, 3H), 2.24 -2.40 (m, 1H), 2.03 -2.19 (m, 1 H). 1.27 -1.47 (m, 2H).
EXAMPLE 95
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-methoxy
phenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 95A
methyl 2-phenyl(1H-pyrazolyl)acetate
The title compound was prepared by substituting dimethyl carbonate for 2-chloro-1,1-
dimethoxyethane in EXAMPLE 77A.
EXAMPLE 95B
methyl 3-bromophenyl(1H-pyrazolyl)acetate
The title compound was prepared by substituting EXAMPLE 95A for EXAMPLE
63B in EXAMPLE 63C.
E 95C
tert-butyl benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(2-
methoxyoxophenylethyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 95B for EXAMPLE
77D in EXAMPLE 77E.
EXAMPLE 95D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-methoxy
oxophenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 95C for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.84 (s, 1H), 8.04 (d,
1H), 7.83 (s, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.64 (s, 1H), 7.61 (d, 1H), 7.31 -7.51 (m, 9H),
6.93 (d, 1H), 6.52 (s, 1H), 4.94 (s, 2H), 3.86 (t, 2H), 3.71 (s, 3H), 2.99 (t, 2H).
EXAMPLE 96
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-cyclohexyl-
ylethyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 96A
1-(2-cyclohexylphenylethyl)-1H-pyrazole
The title compound was ed by substituting cyclohexylmethylbromide for 2-
chloro-1,1-dimethoxyethane in EXAMPLE 77A.
EXAMPLE 96B
1-(2-cyclohexylphenylethyl)iodo-1H-pyrazole
The title nd was prepared by substituting EXAMPLE 96A for EXAMPLE
65E in EXAMPLE 65F.
EXAMPLE 96C
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(2-
cyclohexylphenylethyl)-1H-pyrazolyl)picolinate
The title compound was ed by substituting EXAMPLE 96B for EXAMPLE
77D in EXAMPLE 77E.
EXAMPLE 96D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-cyclohexyl-
1-phenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 96C for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 1H), 8.04 (d,
1H), 7.99 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.61 (d, 1H), 7.56 (s, 1H), 7.44 -7.52 (m, 1H),
7.40-7.44 (m, 1H), 7.22 -7.40 (m, 7H), 6.94 (d, 1H), 5.51 (dd, 1H), 4.94 (s, 2H), 3.86 (t,
2H), 2.99 (t, 2H), 2.15 -2.32 (m, 1H), 1.85 -1.99 (m, 1H), 1.80 (d, 1H), 1.48 -1.71 (m, 4H),
0.86-1.14 (m, 6H).
EXAMPLE 97
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(3-
methoxypropyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 97A
methyl 1-(3-methoxypropyl)cyclohexanecarboxylate
To a cooled (-78oC) solution of lithium diisopropylamide (2.0 M, 12 mL) in
tetrahydrofuran (10 mL) was added methyl cyclohexanecarboxylate (1.42 g) in
tetrahydrofuran (10 mL). The e was stirred at -78oC for 30 minutes and a solution of 1-
bromomethoxypropane (1.73 g) in tetrahydrofuran (10 mL) was added to the mixture. The
mixture was stirred overnight and the ature was allowed to warm up to room
temperature. The mixture was quenched with aqueous NH4Cl and ted with ethyl acetate
(200 mL) and washed with water (3x), brine and dried over Na2SO4. Filtration and
evaporation of the solvent gave the crude product which was used in the next reaction without
further purification.
EXAMPLE 97B
(1-(3-methoxypropyl)cyclohexyl)methanol
A solution of EXAMPLE 97A (2.14 g) in diethyl ether (10 mL) was added dropwise
to a suspension of LiAlH4 (0.380 g) in diethyl ether (20 mL). Once the addition was finished,
the mixture was refluxed for 90 minutes, and then cooled to 0 oC. NaOH (2N, aqueous, 50
mL) was then added slowly. The e was extracted with ethyl acetate (300 mL) and
washed with brine and dried over . Filtration and evaporation of the solvent gave the
title compound.
EXAMPLE 97C
1-((1-(3-methoxypropyl)cyclohexyl)methyl)-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 97B for (3-
(dimethylamino)phenyl)methanol and pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 97D
1-((1-(3-methoxypropyl)cyclohexyl)methyl)methyl-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 97C for EXAMPLE
63A in EXAMPLE 63B.
EXAMPLE 97E
4-bromo((1-(3-methoxypropyl)cyclohexyl)methyl)methyl-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 97D for EXAMPLE
63B in EXAMPLE 63C.
EXAMPLE 97F
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(3-
methoxypropyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by first tuting EXAMPLE 97E for
EXAMPLE 86D in EXAMPLE 86E, and then substituting the t from that reaction for
EXAMPLE 8B in E 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.85
(s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.70 (m, 1H), 7.61 (d, 1H), 7.41 (m, 6 H), 7.28 (s, 1H),
6.95 (d, 1H), 4.95 (s, 3H), 3.88 (m, 4H), 3.27 (t, 2H), 3.02 (m, 2H), 2.10 (s, 3H), 1.30 (m,
14H).
EXAMPLE 98
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[3-hydroxy-
2-(hydroxymethyl)methylpropoxy]benzyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid
EXAMPLE 98A
4-Iodomethyl(2-((3-methyloxetanyl)methoxy)benzyl)-1H-pyrazole
The title nd was prepared by substituting hyloxetanyl)methanol for
2-morpholinoethanol in EXAMPLE 79C.
E 98B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[3-hydroxy-
2-(hydroxymethyl)methylpropoxy]benzyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid
The title compound was prepared by first substituting EXAMPLE 98A for
EXAMPLE 77D in EXAMPLE 77E, and then substituting the product from that reaction for
EXAMPLE 1E in EXAMPLE 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.85
(s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.48 (m, 3H), 7.36 (m, 3H), 7.22 (t, 1H), 6.97
(t, 2H), 6.82 (t, 1H), 6.47 (d, 1H), 5.26 (s, 2H), 4.96 (s, 2H), 3.41 (m, 4H), 3.01 (t, 2H), 2.06
(s, 3H), 0.94 (s, 3H).
EXAMPLE 99
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-methyl[2-
(tetrahydro-2H-pyranylmethoxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
E 99A
4-iodomethyl(2-((tetrahydro-2H-pyranyl)methoxy)benzyl)-1H-pyrazole
The title compound was prepared by substituting hydro-2H-pyranyl)methanol
for 2-morpholinoethanol in EXAMPLE 79C.
EXAMPLE 99B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(5-
methyl(2-((tetrahydro-2H-pyranyl)methoxy)benzyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 99A for EXAMPLE
77D in EXAMPLE 77E.
EXAMPLE 99C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-methyl[2-
(tetrahydro-2H-pyranylmethoxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 99B for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 1H), 8.03 (d,
1H), , 1H), 7.61 (d, 1H), 7.42 (m, 6H), 7.24 (t, 1H), 6.98 (m, 2H), 6.85 (t, 1H), 6.61 (d,
1H), 5.23 (s, 2H), 4.95 (s, 2H), 3.87 (m, 7H), 3.32 (t, 2H), 3.02 (t, 2H), 2.08 (s, 3H), 1.69 (m,
2H), 1.36 (m, 2H).
EXAMPLE 100
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(1,4-
dioxanylmethoxy)benzyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 100A
1-(2-((1,4-dioxanyl)methoxy)benzyl)iodomethyl-1H-pyrazole
The title compound was prepared by substituting (1,4-dioxanyl)methanol for 2-
morpholinoethanol in EXAMPLE 79C.
EXAMPLE 100B
Tert-butyl 3-(1-(2-((1,4-dioxanyl)methoxy)benzyl)methyl-1H-pyrazolyl)(8-
[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinate
The title nd was prepared by substituting EXAMPLE 100A for EXAMPLE
77D in EXAMPLE 77E.
EXAMPLE 100C
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(1,4-
dioxanylmethoxy)benzyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 100B for EXAMPLE
1E in EXAMPLE 1F. 1H NMR (300 MHz, ylsulfoxide-d 6) G ppm 12.86 (s, 1H), 8.03
(d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.42 (m, 6H), 7.24 (t, 1H), 6.99 (m, 2H), 6.87 (t, 1H), 6.65
(d, 1H), 5.23 (s, 2H), 4.96 (m, 2H), 4.02 (m, 2H), 3.83 (m, 5H), 3.65 (m, 2H), 3.46 (m, 2H),
3.01 (t, 2H), 2.10 (s, 3H).
EXAMPLE 101
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethoxy)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 101A
1-oxaspiro[2.5]octane
To a solution of trimethylsulfonium iodide (35.7 g) in dry DMSO (300 mL) was
added cyclohexanone (9.82 g) with stirring. The mixture was brought under N2 here
and a solution of potassium tert-butoxide (16.83 g) in dry DMSO (200 mL) was slowly added.
The resulting solution was stirred at room temperature for 16 hours under N2. The reaction
mixture was quenched by addition of water (600 mL), and ted with diethyl ether (3x
200 mL). The combined organic layers were washed with water (200 mL), dried over Na2SO4,
filtered, and concentrated under reduced pressure to provide the title nd.
EXAMPLE 101B
1-((4-iodomethyl-1H-pyrazolyl)methyl)cyclohexanol
To a solution of 4-iodomethyl-1H-pyrazole (2.08 g) in N,N-dimethylformamide (1
mL) was added EXAMPLE 101A (3.1 g) and Cs2CO3 (5.34 g). The mixture was stirred at
120oC for 5 minutes in a Biotage Initiator microwave reactor. The reaction mixture was
diluted with ethyl acetate (400 mL) and washed with water and brine and dried over Na2SO4.
The mixture was filtered and concentrated under reduced pressure to give crude product
which was loaded on a 120 g silica gel column and eluted with 10% ethyl acetate in hexane to
provide the title compound.
EXAMPLE 101C
4-iodo((1-(2-methoxyethoxy)cyclohexyl)methyl)methyl-1H-pyrazole
To a solution of EXAMPLE 101B (260 mg) in tetrahydrofuran (15 mL) was added
NaH (97 mg). The mixture was stirred for 30 minutes. 1-Bromomethoxyethane (564 mg)
was added to the mixture and the mixture was stirred for 3 hours. The mixture was then
stirred at reflux for 2 hours. Hexamethylphosphoramide (5 mL) and additional NaH (200 mg)
were added to the mixture and the mixture was stirred at reflux overnight. The reaction
mixture was diluted with ethyl acetate (200 mL) and washed with water and brine and dried
over . The residue, after filtration and evaporation of the t, was loaded on a 40
g column and eluted with 20% ethyl acetate in hexane to give the title compound.
EXAMPLE 101D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethoxy)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by first substituting EXAMPLE 101C for
EXAMPLE 77D in EXAMPLE 77E, and then substituting the product from that reaction for
EXAMPLE 1E in EXAMPLE 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.85
(s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.40 (m, 6 H), 7.28 (s, 1H), 6.95 (d, 1H),
4.95 (s, 3H), 4.05 (s, 2H), 3.89 (t, 2H), 3.46 (m, 4H), 3.25 (m, 3H), 3.01 (t, 2H), 2.14 (m, 3H),
1.33 (m, 10 H).
E 102
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](4-
phenoxyphenyl)pyridinecarboxylic acid
EXAMPLE 102A
utyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(4-
phenoxyphenyl)picolinate
The title compound was prepared by substituting 4-phenoxyphenylboronic acid for 1-
benzyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 102B
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](4-
yphenyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 102A for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 2H), 8.04
(d, 1H), 7.79 (d, 1H), 7.66 (d, 1H), 7.62 (d, 1H), 7.31 -7.50 (m, 8H), 7.15 (t, 1H), 6.97 -7.05
(m, 5H), 4.98 (s, 2H), 3.91 (t, 2H), 3.02 (t, 2H).
EXAMPLE 103
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](3-
phenoxyphenyl)pyridinecarboxylic acid
E 103A
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(3-
yphenyl)picolinate
The title compound was prepared by substituting 3-phenoxyphenylboronic acid for 1-
benzyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 103B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](3-
phenoxyphenyl)pyridinecarboxylic acid
The title compound was prepared by tuting EXAMPLE 103A for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 2H), 8.04
(d, 1H), 7.79 (d, 1H), 7.66 (d, 1H), 7.62 (d, 1H), 7.33 -7.50 (m, 7H), 7.08 -7.17 (m, 2H),
7.03 (d, 2H), 6.90 -6.99 (m, 3H), 4.98 (s, 2H), 3.90 (t, 2H), 3.01 (t, 2H).
E 104
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-(4-
nitrophenoxy)phenyl]pyridinecarboxylic acid
EXAMPLE 104A
Methyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)
bromopicolinate
The title compound was prepared by substituting methyl 3-bromochloropicolinate
for tert-butyl 3-bromochloropicolinate in EXAMPLE 1D.
EXAMPLE 104B
Methyl benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(3-(4-
nitrophenoxy)phenyl)picolinate
The title compound was prepared by substituting EXAMPLE 104A for EXAMPLE
1D and 3-(4-nitrophenoxy)phenylboronic acid for 1-benzyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 104C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-(4-
nitrophenoxy)phenyl]pyridinecarboxylic acid
To an ambient solution of EXAMPLE 104B (75 mg) in ydrofuran (1.5 mL) and
water (0.5 mL) was added LiOH H2O (13 mg). The reaction was stirred overnight, diluted
with 2 mL water and 2 mL ethyl acetate, and acidified to pH ~3 with 10% aqueous HCl
solution. The layers were separated, and the aqueous layer was extracted with additional
ethyl acetate (2 x 8 mL). The combined organic layers were dried with anhydrous sodium
sulfate, filtered and concentrated under reduced pressure to provide the title compound.. 1H
NMR (300 MHz, dimethylsulfoxide-d6) G ppm 12.85 (s, 1H), 8.26 (m, 2H), 8.03 (d, 1H), 7.79
(d, 1H), 7.71 (d, 1H), 7.62 (d, 1H), 7.43 (m, 5H), 7.26 (d, 1H), 7.14 (m, 4H), 7.00 (d, 1H),
4.99 (s, 2H), 3.91 (t, 2H), 3.01 (t, 2H).
EXAMPLE 105
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-(4-
chlorophenoxy)phenyl]pyridinecarboxylic acid
EXAMPLE 105A
2-(3-(4-chlorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolanyl)phenol (0.23 g), copper(II) acetate (0.19 g),
triethylamine (0.218 g) and 4-chlorophenylboronic acid (0.237 g) were stirred at room
temperature overnight. The solid was filtered off, and the t was removed under reduced
pressure. The crude product was purified by flash chromatography(Varian, Superflash SF25-
40 g ), eluting 25% ethyl acetate/hexane, to providethe title compound.
EXAMPLE 105B
tert-butyl benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(3-(4-
chlorophenoxy)phenyl)picolinate
The title nd was prepared by substituting EXAMPLE 105A for 1-benzyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 105C
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-(4-
chlorophenoxy)phenyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 105B for EXAMPLE
1E in EXAMPLE 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 1H), 8.04
(d, 1H), 7.79 (d, 1H), 7.64 (m, 2H), 7.41 (m, 7H), 7.05 (m, 6H), 4.98 (s, 2H), 3.90 (t, 2H),
3.01 (t, 2H).
EXAMPLE 106
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](3-
benzylphenyl)pyridinecarboxylic acid
EXAMPLE 106A
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(3-
benzylphenyl)picolinate
The title compound was prepared by substituting 3-benzylphenylboronic acid for 1-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 106B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](3-
benzylphenyl)pyridinecarboxylic acid
The title compound was prepared by tuting E 106A for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.87 (s, 2H), 8.04
(d, 1H), 7.80 (d, 1H), 7.62 (d, 2H), 7.41 -7.50 (m, 2H), 7.33 - 7.39 (m, 2H), 7.20-7.31 (m,
6H), 7.12 -7.19 (m, 3H), 6.98 (d, 1H), 4.98 (s, 2H), 3.86 -3.96 (m, 4H), 3.01 (t, 2H).
EXAMPLE 107
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexylmethyl)methylphenyl]pyridinecarboxylic acid
EXAMPLE 107A
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(3-
chloromethylphenyl)picolinate
The title compound was prepared by substituting 3-chloromethylphenylboronic
acid for yl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE
EXAMPLE 107B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(3-
hexylmethyl)methylphenyl)picolinate
A mixture of EXAMPLE 107A (60 mg), dicyclohexyl(2',6'-diisopropoxybiphenyl
yl)phosphine (RuPhos, 4.58 mg) and tris(dibenzylideneacetone)dipalladium(0) (2.25 mg) in
tetrahydrofuran (0.5 mL) and 1-methylpyrrolidinone (0.5 mL) was stirred at room
temperature for 5 minutes while bubbling N2 through the reaction mixture. To this solution
was added 0.5 M (cyclohexylmethyl)zinc(II) bromide (0.393 mL) at room temperature. The
reaction mixture in a sealed tube was heated in a preheated oil bath at 100ºC overnight and
cooled. The reaction mixture was quenched with water and diluted with dichloromethane.
The dichloromethane layer was washed with water and trated. The residue was
purified by flash chromatography, and eluted with 5% ethyl acetate in dichloromethane to
provide the title compound.
EXAMPLE 107C
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexylmethyl)methylphenyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 107B for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (s, 1H), 8.03
(d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.42 -7.49 (m, 3H), 7.32 - 7.40 (m, 2H), 7.02 -7.06 (m,
2H), 6.97 (d, 1H), 6.84 (dd, 1H), 4.98 (d, 2H), 3.92 (t, 2H), 3.03 (t, 2H), 1.97 (s, 3H), 1.40 -
1.70 (m, 7H), 0.91 - 1.26 (m, 6H).
EXAMPLE 108
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](4-methyl
yphenyl)pyridinecarboxylic acid
EXAMPLE 108A
4-bromomethylphenoxybenzene
A mixture of 5-bromomethylphenol (1.0 g), phenylboronic acid (1.30 g),
Cu(OAc)2 (0.97 g), and triethylamine (2.98 mL) in dichloromethane (50 mL) was stirred for 4
days. The mixture was diluted with ethyl acetate, washed four times with 1M aqueous NaOH
solution and once with brine, dried over Na2SO4, filtered, and concentrated. The crude
product was chromatographed on silica gel using 2% ethyl acetate in hexanes to afford the
title compound.
EXAMPLE 108B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(4-
methylphenoxyphenyl)picolinate
A mixture of EXAMPLE 30A (172 mg), EXAMPLE 108A (74 mg), and [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg) in e (6 mL) and 2M
aqueous Na2CO3 solution (3 mL) was stirred at 60oC for 18 hours. The mixture was
chromatographed on silica gel using 2-20% ethyl e in hexanes to afford the title
compound.
EXAMPLE 108C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](4-methyl
yphenyl)pyridinecarboxylic acid
The title compound was prepared by substituting E 108B for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (br s, 2H),
8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 2H), 7.49 (dd, 1H), 7.43 (dd, 1H), 7.30 -7.38 (m, 3H),
7.25 (dd, 1H), 7.16 (dd, 1H), 7.06 (m, 2H), 6.95 (d, 1H), 6.91 (d, 1H), 6.87 (m, 2H), 4.96 (s,
2H), 3.88 (t, 2H), 2.99 (t, 2H), 2.16 (s, 3H).
E 109
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-methyl
phenoxyphenyl)pyridinecarboxylic acid
EXAMPLE 109A
2-bromomethylphenoxybenzene
The title compound was prepared by substituting 3-bromomethylphenol for 5-
bromomethylphenol in EXAMPLE 108A.
EXAMPLE 109B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(2-
methylphenoxyphenyl)picolinate
The title compound was prepared by substituting E 109A for EXAMPLE
108A in EXAMPLE 108B.
EXAMPLE 109C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-methyl
phenoxyphenyl)pyridinecarboxylic acid
The title compound was ed by substituting EXAMPLE 109B for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.55 (br s, 1H),
12.00 (br s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.51 (dd, 1H), 7.45 (dd, 2H), 7.35
(m, 4H), 7.23 (dd, 1H), 7.08 (t, 1H), 6.96 (m, 3H), 6.87 (dd, 1H), 6.68 (d, 1H), 4.97 (s, 2H),
3.91 (t, 2H), 3.02 (t, 2H), 2.04 (s, 3H).
E 110
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-methyl
phenoxyphenyl)pyridinecarboxylic acid
EXAMPLE 110A
1-bromomethylphenoxybenzene
The title compound was prepared by substituting 3-bromomethylphenol for 5-
bromomethylphenol in EXAMPLE 108A.
EXAMPLE 110B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(2-
methylphenoxyphenyl)picolinate
The title compound was prepared by substituting EXAMPLE 110A for EXAMPLE
108A in EXAMPLE 108B.
EXAMPLE 110C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-methyl
phenoxyphenyl)pyridinecarboxylic acid
The title compound was prepared by substituting E 110B for EXAMPLE
8B in E 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (br s, 1H),
12.00 (br s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.54 (d, 1H), 7.47 (dd, 2H), 7.34 (m,
4H), 7.24 (dd, 1H), 7.18 (dd, 1H), 7.06 (t, 1H), 7.01 (dd, 2H), 6.90 (m, 3H), 4.99 (s, 2H), 3.93
(t, 2H), 3.03 (t, 2H), 1.90 (s, 3H).
EXAMPLE 111
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-methyl
phenoxyphenyl)pyridinecarboxylic acid
EXAMPLE 111A
1-bromomethylphenoxybenzene
The title compound was prepared by substituting 4-bromomethylphenol for 5-
2-methylphenol in EXAMPLE 108A.
EXAMPLE 111B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(2-
methylphenoxyphenyl)picolinate
The title nd was prepared by substituting E 111A for EXAMPLE
108A in EXAMPLE 108B.
EXAMPLE 111C
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-methyl
phenoxyphenyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 111B for EXAMPLE
8B in E 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (br s, 1H),
12.00 (br s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.32-7.51 (m, 7H), 7.14 (t, 1H), 7.03
(m, 3H), 6.98 (d, 1H), 6.88 (d, 1H), 6.78 (dd, 1H), 4.98 (s, 2H), 3.92 (t, 2H), 3.03 (t, 2H), 1.91
(s, 3H).
EXAMPLE 112
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexylmethoxy)methylphenyl]pyridinecarboxylic acid
EXAMPLE 112A
1-Bromocyclohexylmethoxymethyl-benzene
The title compound was prepared by substituting cyclohexylmethanol for (3-
hylamino)phenyl)methanol and 3-bromomethylphenol for 4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 112B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexylmethoxy)methylphenyl]pyridinecarboxylic acid utyl ester
EXAMPLE 30A (125 mg), EXAMPLE 112A (87 mg), trans-
dichlorobis(triphenylphosphine)palladium (II) (29 mg), and cesium carbonate (266 mg) were
added to a microwave vial. N,N-dimethylformamide (0.9 mL), 1,4-dioxane (0.6 mL), and
water (0.3 mL) were added. The vial was placed in a microwave reactor and subjected to
120°C for 15 minutes. The solution was then added to water and extracted with 30% ethyl
acetate in hexanes. The extract was washed with brine and dried over anhydrous sodium
sulfate. The solution was filtered, concentrated and purified on silica gel using 30% ethyl
acetate in hexanes.
EXAMPLE 112C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexylmethoxy)methylphenyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 112B for EXAMPLE
7D in EXAMPLE 7E. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (bs, 1H), 8.04
(d, 1H), 7.89 (d, 1H), 7.63 (d, 1H), 7.50-7.32 (m, 5H), 7.08 (t, 1H), 6.98 (d, 1H), 6.86 (d, 1H),
6.62 (d, 1H), 4.98 (s, 2H), 3.92 (t, 2H), 3.77 (d, 2H), 3.03 (t, 2H), 1.90 (s, 3H), 1.88-1.62 (m,
6H), 1.31-1.03 (m, 5H).
EXAMPLE 113
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][4-
(cyclohexyloxy)methylphenyl]pyridinecarboxylic acid
E 113A
ocyclohexyloxymethyl-benzene
The title compound was prepared by substituting cyclohexanol for (3-
(dimethylamino)phenyl)methanol and 4-bromomethylphenol for 4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 113B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][4-
hexyloxy)methylphenyl]pyridinecarboxylic acid tert-butyl ester
The title compound was ed by substituting EXAMPLE 113A for EXAMPLE
112A in EXAMPLE 112B.
EXAMPLE 113C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][4-
(cyclohexyloxy)methylphenyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 113B for EXAMPLE
7D in EXAMPLE 7E. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (bs, 1H), 8.04
(d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.51-7.34 (m, 5H), 6.97-6.89 (m, 2H), 6.79 (dd, 1H), 6.71
(dd, 1H), 4.97 (s, 2H), 4.30 (m, 1H), 3.91 (t, 2H), 3.02 (t, 2H), 2.02 (s, 3H), 1.97-1.85 (m,
2H), 1.78-1.62 (m, 2H), 1.58-1.20 (m, 6H).
EXAMPLE 114
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexyloxy)methylphenyl]pyridinecarboxylic acid
EXAMPLE 114A
1-bromocyclohexyloxymethyl-benzene
The title compound was prepared by substituting exanol for (3-
(dimethylamino)phenyl)methanol and 3-bromomethylphenol for 4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 114B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexyloxy)methylphenyl]pyridinecarboxylic acid tert-butyl ester
The title compound was prepared by substituting EXAMPLE 114A for EXAMPLE
112A in EXAMPLE 112B.
E 114C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexyloxy)methylphenyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 114B for EXAMPLE
7D in EXAMPLE 7E. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (bs,1H), 8.03
(d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.51-7.32 (m, 5H), 7.07 (t, 1H), 6.97 (d, 1H), 6.91 (d, 1H),
6.61 (d, 1H), 4.98 (s, 2H), 4.33 (m, 1H), 3.92 (t, 2H), 3.03 (t, 2H), .84 (m, 2H), 1.89 (s,
3H), 1.77-1.63 (m, 2H), 1.57-1.26 (m, 6H).
EXAMPLE 115
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][4-
(cyclohexylmethoxy)methylphenyl]pyridinecarboxylic acid
EXAMPLE 115A
1-Bromocyclohexylmethoxymethyl-benzene
The title compound was prepared by substituting cyclohexylmethanol for (3-
(dimethylamino)phenyl)methanol and 4-bromomethylphenol for 4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 115B
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][4-
(cyclohexylmethoxy)methylphenyl]pyridinecarboxylic acid tert-butyl ester
The title compound was ed by substituting EXAMPLE 115A for EXAMPLE
112A in EXAMPLE 112B.
EXAMPLE 115C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][4-
(cyclohexylmethoxy)methylphenyl]pyridinecarboxylic acid
The title compound was ed by substituting EXAMPLE 115B for EXAMPLE
7D in EXAMPLE 7E. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (bs, 1H), 8.04
(d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.51-7.32 (m, 5H), 6.96 (d, 1H), 6.91 (d, 1H), 6.79 (d,
1H), 6.70 (d, 1H), 4.97 (s, 2H), 3.91 (t, 2H), 3.75 (d, 2H), 3.03 (t, 2H), 2.02 (s, 3H), 1.87-1.59
(m, 6H), 1.31-1.00 (m, 5H).
EXAMPLE 116
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-cyano
(cyclohexyloxy)phenyl]pyridinecarboxylic acid
EXAMPLE 116A
2-bromo(cyclohexyloxy)benzonitrile
To a solution of cyclohexanol (0.275 g) in N,N-dimethylformamide (5 mL) was
added sodium hydride (60%, 0.069 g). After 30 minutes, 2-bromofluorobenzonitrile
(0.500 g) was added and the reaction stirred at room temperature for 2 hours. The reaction
mixture was diluted with ethyl acetate (25 mL), washed with water (20 mL) and brine (20
mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography
eluting with a gradient of 3% to 10% ethyl acetate/hexanes ed the title compound.
EXAMPLE 116B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-cyano
(cyclohexyloxy)phenyl]pyridinecarboxylic acid
The title compound was prepared by first substituting EXAMPLE 116A for
EXAMPLE 112A in E 112B, and then substituting the t from that reaction
for EXAMPLE 8B in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm
12.79 (s, 2H), 8.03 (d, 1H), 7.79 (d, 1H), 7.63 (d, 2H), 7.55 (dd, 1H), 7.51 -7.31 (m, 4H),
7.21 (d, 1H), 7.04 (d, 1H), 6.87 (d, 1H), 5.03 (s, 2H), 4.59 (s, 1H), 3.97 (d, 2H), 3.04 (s, 2H),
1.91 (s, 2H), 1.71 (s, 2H), 1.62 -1.26 (m, 6H).
EXAMPLE 117
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-chloro
(cyclohexyloxy)phenyl]pyridinecarboxylic acid
EXAMPLE 117A
1-bromochloro(cyclohexyloxy)benzene
The title compound was prepared by substituting for cyclohexanol for (3-
(dimethylamino)phenyl)methanol and ochlorophenol for 4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 34A.
E 117B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-chloro
hexyloxy)phenyl]pyridinecarboxylic acid
The title compound was prepared by first substituting EXAMPLE 117A for
EXAMPLE 112A in EXAMPLE 112B, and then substituting the product from that reaction
for EXAMPLE 8B in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm
12.79 (s, 2H), 8.03 (d, 1H), 7.79 (d, 1H), 7.63 (d, 2H), 7.55 (dd, 1H), 7.51 -7.31 (m, 4H),
7.21 (d, 1H), 7.04 (d, 1H), 6.87 (d, 1H), 5.03 (s, 2H), 4.59 (s, 1H), 3.97 (d, 2H), 3.04 (s, 2H),
1.91 (s, 2H), 1.71 (s, 2H), 1.62 - 1.26 (m, 6H).
EXAMPLE 118
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
hexylamino)methylphenyl]pyridinecarboxylic acid
EXAMPLE 118A
(3-Bromomethyl-phenyl)-cyclohexyl-amine
The title nd was prepared by substituting cyclohexanone for EXAMPLE 64B
and 3-bromomethylaniline for dimethylamine in EXAMPLE 68A.
EXAMPLE 118B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexylamino)methylphenyl]pyridinecarboxylic acid tert-butyl ester
The title compound was prepared by substituting E 118A for EXAMPLE
112A in EXAMPLE 112B.
EXAMPLE 118C
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexylamino)methylphenyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 118B for EXAMPLE
7D in EXAMPLE 7E. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (bs, 1H), 8.03
(d, 1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.50-7.32 (m, 6H), 7.26-7.10 (m, 2H), 6.99 (d, 1H), 4.99
(s, 2H), 3.93 (t, 2H), 3.29 (bs, 1H), 3.03 (t, 2H), 2.08-1.83 (m, 2H), 1.96 (bs, 3H), 1.80-1.70
(m, 2H), 1.66-1.57 (m, 1H), 1.45-1.15 (m, 5H).
EXAMPLE 119
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexyloxy)fluorophenyl]pyridinecarboxylic acid
EXAMPLE 119A
1-Bromocyclohexyloxyfluoro-benzene
The title compound was prepared by tuting cyclohexanol for (3-
(dimethylamino)phenyl)methanol and 3-bromofluorophenol for 4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 119B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
hexyloxy)fluorophenyl]pyridinecarboxylic acid tert-butyl ester
The title compound was prepared by substituting EXAMPLE 119A for EXAMPLE
112A in EXAMPLE 112B.
E 119C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexyloxy)fluorophenyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 119B for EXAMPLE
7D in EXAMPLE 7E. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (bs, 1H), 8.04
(d, 1H), 7.80 (d, 1H), 7.65-7.58 (m, 2H), 7.51-7.32 (m, 5H), 7.15-6.99 (m, 2H), 6.80 (td, 1H),
.00 (s, 2H), 4.32 (m, 1H), 3.94 (t, 2H), 3.02 (t, 2H), 1.98-1.87 (m, 2H), 1.77-1.66 (m, 2H),
1.58-1.22 (m, 6H).
EXAMPLE 120
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
hexyloxy)(trifluoromethyl)phenyl]pyridinecarboxylic acid
EXAMPLE 120A
1-Bromocyclohexyloxytrifluoromethyl-benzene
Cyclohexanol (214 mg) was added to N,N-dimethylacetamide (10 mL), and sodium
hydride (60% in mineral oil, 86 mg) was added. The solution was mixed at room temperature
for 15 minutes after which time ofluoro(trifluoromethyl)benzene (400 mg) was
added. The solution was then heated at 100°C for 1 hour. The solution was , added to
water, and extracted with diethyl ether. The extract was washed with brine, dried over
anhydrous sodium sulfate, and ed. The filtrate was concentrated and purified on silica
gel using 5% ethyl acetate in hexanes.
EXAMPLE 120B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexyloxy)(trifluoromethyl)phenyl]pyridinecarboxylic acid tert-butyl ester
The title compound was prepared by substituting EXAMPLE 120A for EXAMPLE
112A in EXAMPLE 112B.
EXAMPLE 120C
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-
(cyclohexyloxy)(trifluoromethyl)phenyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 120B for EXAMPLE
7D in EXAMPLE 7E. 1H NMR (400 MHz, ylsulfoxide-d 6) G ppm 12.85 (bs, 1H), 8.03
(d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.50-7.32 (m, 6H), 7.22 (d, 1H), 6.99 (d, 1H), 6.64 (d,
1H), 4.99 (s, 2H), 4.57 (m, 1H), 3.94 (t, 2H), 3.03 (t, 2H), 1.93-1.80 (m, 2H), 1.78-1.63 (m,
2H), 1.60-1.18 (m, 6H).
EXAMPLE 121
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-[(3,3-
dimethylcyclohexyl)oxy]methylphenyl}pyridinecarboxylic acid
EXAMPLE 121A
1-bromo(3,3-dimethyl-cyclohexyloxy)methyl-benzene
The title compound was prepared by substituting 3,3-dimethylcyclohexanol for (3-
(dimethylamino)phenyl)methanol and 3-bromomethylphenol for 4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 121B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-[(3,3-
ylcyclohexyl)oxy]methylphenyl}pyridinecarboxylic acid tert-butyl ester
The title compound was prepared by substituting E 121A for EXAMPLE
112A in E 112B.
EXAMPLE 121C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-[(3,3-
dimethylcyclohexyl)oxy]methylphenyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 121B for EXAMPLE
7D in EXAMPLE 7E. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (bs, 1H), 8.03
(d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.56-7.32 (m, 5H), 7.08 (t, 1H), 6.97 (d, 1H), 6.91 (d, 1H),
6.61 (d, 1H), 4.98 (s, 2H), 4.40 (m, 1H), 3.92 (t, 2H), 3.03 (t, 2H), 2.08-1.98 (m, 2H), 1.86 (s,
3H), 1.81-1.72 (m, 2H), .45(m, 2H), 1.37-1.20 (m, 2H), 0.96 (s, 6H).
E 122
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H-
1,2,3-triazolyl)pyridinecarboxylic acid
E 122A
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)
ethynylpicolinate
To a 50 mL pressure flask was added EXAMPLE 1D (1.0 g), ethynyltrimethylsilane
(2.50 mL), and triethylamine (1.23 mL) in tetrahydrofuran (18 mL).
Bis(triphenylphosphine)palladium(II) dichloride (0.124 g) and CuI (0.034 g) were added, and
the flask was flushed with nitrogen and sealed. The reaction was heated to 85oC for 36 hours,
cooled and passed through a plug of silica gel. After rinsing the silica gel with
dichloromethane, the combined tes were concentrated by rotary evaporation, taken up in
tetrahydrofuran (20 mL). tetra-n-Butylammonium fluoride (1M in tetrahydrofuran, 1.48 mL)
was added dropwise at room temperature. The reaction was allowed to stir for 2 hours.
Saturated aqueous NH4Cl solution was added and the aqueous n was extracted three
times with dichloromethane. The combined organics were dried over Na2SO4, filtered and
concentrated. The residue was purified by r phase flash column chromatography
(Analogix, 0-100% ethyl acetate in hexanes) to provide the title compound.
EXAMPLE 122B
tert-butyl benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
benzyl-1H-1,2,3-triazolyl)picolinate
To a 4 mL vial was added E 122A (30 mg), benzyl bromide (10.05 mg),
and NaN3 (4.58 mg) in N,N-dimethylformamide (0.5 mL) and water (0.12 mL). Sodium
ascorbate (1.7 mg) and copper (II) sulfate pentahydrate (0.733 mg) was added and the mixture
was heated at 70oC overnight, cooled, and tographed by regular phase flash column
chromatography (Analogix, 0-100% ethyl acetate in hexanes) to provide the title compound.
EXAMPLE 122C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H-
1,2,3-triazolyl)pyridinecarboxylic acid
To a 10 mL round-bottomed flask was added EXAMPLE 122B (150 mg) in
dichloromethane (2.3 mL). TFA (1.2 mL) was added and the mixture was stirred for 2 hours.
The volatiles were removed under a stream of N2. The residue was placed on high-vacuum
for 1 hour and then purified by regular phase flash column chromatography (Analogix, 0-
100% ethyl acetate in hexanes) to provide the title compound. 1H NMR (300 MHz,
dimethylsulfoxide-d6) δ ppm 13.07 (s, 1H), 8.21 (s, 1H), 8.04 (d, 1H), 7.98 (d, 1H), 7.79 (d,
1H), 7.62 (d, 1H), 7.51 – 7.27 (m, 9H), 6.98 (d, 1H), 5.62 (s, 2H), 4.98 (s, 2H), 3.90 (t, 2H),
3.01 (t, 2H).
EXAMPLE 123
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-benzyl
(ethoxycarbonyl)methyl-1H-pyrrolyl]pyridinecarboxylic acid
EXAMPLE 123A
ethyl 1-benzylmethyl-1H-pyrrolecarboxylate
Ethyl 5-methyl-1H-pyrrolecarboxylate (1.1 g) and benzyl bromide (1.35 g) in N,N-
dimethylformamide (30 mL) was treated with NaH (95%, 0.5 g) ght. The reaction was
ed with ice water. The mixture was diluted with ethyl acetate and washed with brine.
The organic layer was dried over Na2SO4, filtered, and concentrated to provide the title
compound.
EXAMPLE 123B
ethyl 1-benzyliodomethyl-1H-pyrrolecarboxylate
To a solution of EXAMPLE 123A (564 mg) in acetone (8 mL) at 0oC was added N-
iodosuccinimide (600 mg). The mixture was stirred at room temperature overnight, and
diluted with ethyl acetate and washed with water. The c layer was concentrated and the
residue was purified by flash tography, and eluted with 50% dichloromethane in
hexane to e the title compound.
EXAMPLE 123C
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
(ethoxycarbonyl)methyl-1H-pyrrolyl)picolinate
The title compound was prepared by substituting EXAMPLE 123B for EXAMPLE
112A in EXAMPLE 112B.
EXAMPLE 123D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-benzyl
(ethoxycarbonyl)methyl-1H-pyrrolyl]pyridinecarboxylic acid
The title compound was ed by substituting EXAMPLE 123C for E
8B in EXAMPLE 8C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 2H), 8.04
(d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.52 (d, 1H),7.42 -7.50 (m, 2H), 7.27 -7.40 (m, 4H),
7.22 (t, 1H), 6.91 -6.96 (m, 3H), 6.86 (s, 1H), 5.63 (s, 2H), 4.96 (s, 2H), 4.12 (q, 2H), 3.89 (t,
2H), 3.01 (t, 2H), 2.01 (s, 3H), 1.19 (t, 3H).
E 124
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl
carboxymethyl-1H-pyrrolyl)pyridinecarboxylic acid
EXAMPLE 123D (30 mg) in tetrahydrofuran (3 mL) and methanol (3 mL) was
treated with 2N aqueous NaOH (3 mL) ght. The mixture was acidified to a pH of 5
with 1M aqueous HCl and concentrated. The residue was purified by RP-HPLC to provide
the title compound. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 2H), 8.04 (d,
1H), 7.79 (d, 1H), 7.61 (d, 1H),7.41-7.53 (m, 3H), 7.27 -7.39 (m, 4H), 7.22 (t, 1H), 6.91 -
6.97 (m, 3H), 6.83 (s, 1H), 5.65 (s, 2H), 4.95 (s, 2H), 3.89 (t, 2H), 3.01 (t, 2H), 1.99 (s, 3H).
EXAMPLE 125
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H-
pyrrolyl)pyridinecarboxylic acid
EXAMPLE 125A
1-benzyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrrole
The title compound was prepared by substituting 3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrrole for and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazole and benzyl bromide for EXAMPLE 4A in EXAMPLE 4B.
EXAMPLE 125B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
benzyl-1H-pyrrolyl)picolinate
The title compound was ed by substituting EXAMPLE 125A for 1-benzyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 125C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H-
pyrrolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 125B for EXAMPLE
1E in EXAMPLE 1F. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 1H), 8.04
(d, 1H), 7.79 (d, 1H), 7.67 (d, 1H), 7.60 (d, 1H), 7.45 (m, 2H), 7.34 (m, 4H), 7.23 (m, 3H),
6.96 (t, 1H), 6.89 (d, 1H), 6.81 (m, 1H), 6.19 (m, 1H), 5.08 (s, 2H), 4.91 (s, 2H), 3.84 (t, 2H),
2.99 (t, 2H).
E 126
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(4-
methylphenyl)sulfonyl]-1H-pyrrolyl}pyridinecarboxylic acid
EXAMPLE 126A
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-tosyl-
1H-pyrrolyl)picolinate
The title compound was prepared by substituting 3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)tosyl-1H-pyrrole for 1-benzyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 126B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(4-
methylphenyl)sulfonyl]-1H-pyrrolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 126A for EXAMPLE
1E in EXAMPLE 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.84 (s, 1H), 8.03
(d, 1H), 7.78 (m, 4H), 7.60 (d, 1H), 7.41 (m, 9H), 6.90 (d, 1H), 6.49 (m, 1H), 4.94 (s, 2H),
3.86 (t, 2H), 2.99 (t, 2H), 2.37 (s, 3H).
EXAMPLE 127
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzoyl-1H-
pyrrolyl)pyridinecarboxylic acid
E 127A
utyl benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
benzoyl-1H-pyrrolyl)picolinate
The title compound was prepared by substituting phenyl(3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrrolyl)methanone for 1-benzyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole in EXAMPLE 1E.
EXAMPLE 127B
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzoyl-1H-
pyrrolyl)pyridinecarboxylic acid
The title compound was prepared by substituting E 127A for EXAMPLE
1E in EXAMPLE 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 1H), 8.04
(d, 1H), 7.70 (m, 8H), 7.38 (m, 6H), 6.94 (d, 1H), 6.57(m, 1H), 4.95 (s, 2H), 3.87 (t, 2H),
3.01 (t, 2H).
E 128
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(phenylsulfonyl)-1H-pyrrolyl]pyridinecarboxylic acid
EXAMPLE 128A
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
(phenylsulfonyl)-1H-pyrrolyl)picolinate
The title compound was prepared by substituting 1-(phenylsulfonyl)(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrrole for 1-benzyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole in E 1E.
EXAMPLE 128B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-
(phenylsulfonyl)-1H-pyrrolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 128A for EXAMPLE
1E in EXAMPLE 1F. 1H NMR (300 MHz, ylsulfoxide-d 6) G ppm 12.83 (s, 1H), 8.04
(d, 1H), 7.95 (m, 2H), 7.76 (m, 3H),7.63 (m, 3H), 7.41 (m, 6H), 6.91 (d, 1H), 6.51 (m, 1H),
4.94 (s, 2H), 3.86 (t, 2H), 2.99 (t, 2H).
EXAMPLE 129
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl
cyanomethyl-1H-pyrrolyl)pyridinecarboxylic acid
EXAMPLE 129A
1-benzyliodomethyl-1H-pyrrolecarboxylic acid
EXAMPLE 123B (0.5 g) in ydrofuran (20 mL) and methanol (10 mL) was
treated with 2 N NaOH (10 mL) overnight. The reaction mixture was cooled to 0oC,
acidified to pH 5, diluted with water (30 mL) and concentrated to remove the organic solvent.
The precipitates were collected by filtration, washed with water and dried over sodium sulfate
to provide the title compound.
EXAMPLE 129B
1-benzyliodomethyl-1H-pyrrolecarboxamide
To a solution of EXAMPLE 129A (450 mg) in tetrahydrofuran (12 mL) at 0oC was
added carbonyldiimidazole (642 mg). The resulting mixture was stirred at room temperature
for 2 hours. The reaction mixture was cooled to 0oC and ammonium hydroxide (3 mL) was
added. The mixture was stirred at room temperature for 2 hours and concentrated. The
residue was dissolved in ethyl acetate, washed with brine and concentrated to provide the title
compound.
EXAMPLE 129C
1-benzyliodomethyl-1H-pyrrolecarbonitrile
To a solution of EXAMPLE 129B (400 mg) in N,N-dimethylformamide (6 mL) and
ne (0.6 mL) at 0ºC was added dropwise oxalyl chloride (0.31 mL). The e was
stirred at room ature for 30 minutes, diluted with ethyl acetate and washed with
ted NaHCO3 and water extensively. The organic layer was dried over Na2SO4, filtered,
and concentrated. The residue was purified by flash tography, and eluted with
dichloromethane to provide the title compound.
EXAMPLE 129D
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
benzylcyanomethyl-1H-pyrrolyl)picolinate
The title compound was prepared by tuting EXAMPLE 129C for EXAMPLE
112A in EXAMPLE 112B.
EXAMPLE 129E
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl
cyanomethyl-1H-pyrrolyl)pyridinecarboxylic acid
The title nd was prepared by substituting EXAMPLE 129D for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (s, 1H), 8.03
(d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.52 (d, 1H), 7.41 -7.50 (m, 2H), 7.28 -7.40 (m, 5H),
7.04 (d, 2H), 6.96 (d, 1H), 6.90 (s, 1H), 5.30 (s, 2H), 4.96 (s, 2H), 3.89 (t, 2H), 3.01 (t, 2H),
2.05 (s, 3H).
E 130
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-cyano
(cyclohexylmethyl)methyl-1H-pyrrolyl]pyridinecarboxylic acid
EXAMPLE 130A
ethyl 4-iodomethyl-1H-pyrrolecarboxylate
The title compound was prepared by following the procedure described for
EXAMPLE 123B, replacing EXAMPLE 123A with ethyl 5-methyl-1H-pyrrole
carboxylate.
EXAMPLE 130B
4-iodomethyl-1H-pyrrolecarboxylic acid
The title compound was prepared by following the procedure described for
EXAMPLE 129A and replacing EXAMPLE 123B with EXAMPLE 130A.
EXAMPLE 130C
4-iodomethyl-1H-pyrrolecarboxamide
The title compound was prepared by following the procedure described for
EXAMPLE 129B and replacing EXAMPLE 129A with EXAMPLE 130B.
EXAMPLE 130D
4-iodomethyl-1H-pyrrolecarbonitrile
The title compound was prepared by following the procedure described for
EXAMPLE 129C, replacing EXAMPLE 129B with EXAMPLE 130C.
EXAMPLE 130E
1-(cyclohexylmethyl)iodomethyl-1H-pyrrolecarbonitrile
EXAMPLE 130D (100 mg), (bromomethyl)cyclohexane (382 mg) and
tetrabutylammonium bromide (159 mg) in N,N-dimethylformamide was treated with sodium
hydride (86 mg) and stirred at at 50oC overnight. The reaction mixture was cooled, diluted
with ethyl acetate and washed with brine. The organic layer was trated. The residue
was purified by flash chromatography (40% dichloromethane in hexanes) to provide the title
compound.
EXAMPLE 130F
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(5-
cyano(cyclohexylmethyl)methyl-1H-pyrrolyl)picolinate
The title compound was prepared by substituting EXAMPLE 130E for EXAMPLE
112A in EXAMPLE 112B.
EXAMPLE 130G
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-cyano
(cyclohexylmethyl)methyl-1H-pyrrolyl]pyridinecarboxylic acid
The title compound was ed by substituting EXAMPLE 130F for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 1H), 8.04
(d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.41 -7.52 (m, 3H), 7.31 - 7.40 (m, 2H), 6.95 (d, 1H),
6.79 (s, 1H), 4.96 (s, 2H), 3.80 -3.94 (m, 4H), 3.01 (t, 2H), 2.09 (s, 3H), 1.45 -1.77 (m, 6H),
1.10-1.24 (m, 3H), 0.94 -1.06 (m, 2H).
EXAMPLE 131
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano
{[1-(piperidinyl)cyclohexyl]methyl}-1H-pyrrolyl)pyridinecarboxylic acid
E 131A
(1-(piperidinyl)cyclohexyl)methanol
The title compound was prepared by tuting ylcyclohexanecarboxylic acid
with eridinyl)cyclohexanecarboxylic acid in EXAMPLE 67A.
EXAMPLE 131B
4-iodomethyl((1-(piperidinyl)cyclohexyl)methyl)-1H-pyrrolecarbonitrile
The title compound was prepared by substituting EXAMPLE 131A for (3-
(dimethylamino)phenyl)methanol and EXAMPLE 130D for 4-(4,4,5,5-tetramethyl-1,3,2-
orolanyl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 131C
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(5-
cyanomethyl((1-(piperidinyl)cyclohexyl)methyl)-1H-pyrrolyl)picolinate
The title compound was prepared by substituting EXAMPLE 131B for EXAMPLE
112A in EXAMPLE 112B
EXAMPLE 131D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano
methyl{[1-(piperidinyl)cyclohexyl]methyl}-1H-pyrrolyl)pyridinecarboxylic acid
The title compound was ed by substituting EXAMPLE 131C for EXAMPLE
1E in EXAMPLE 1F. 1H NMR (500 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 2H), 8.26
(s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.52 (d, 1H), 7.42 -7.50 (m, 2H), 7.33 -7.40
(m, 2H), 6.97 (d, 2H), 4.90 -5.06 (m, 2H), 4.46 (s, 2H), 3.90 (t, 2H), 3.25 (s, 2H), 3.02 (t,
2H), 1.92 -2.20 (m, 7H), 1.57 - 1.93 (m, 6H), 1.19 -1.55 (m, 5H).
EXAMPLE 132
6,6'-bis[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3,3'-
bipyridine-2,2'-dicarboxylic acid
EXAMPLE 132A
di-tert-butyl is(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-
ipyridine-2,2'-dicarboxylate
The title compound was isolated during the synthesis of EXAMPLE 79D as a
byproduct.
EXAMPLE 132B
6,6'-bis[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3,3'-
bipyridine-2,2'-dicarboxylic acid
The title compound was ed by substituting EXAMPLE 132A for EXAMPLE
1E in EXAMPLE 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.83 (br.s, 2H),
8.02 (d, 2H), 7.77 (d, 2H), 7.60 (d, 2H), 7.40 (m, 10H), 6.97 (d, 2H), 4.97 (s, 4H), 3.92 (t,
4H), 3.01 (t, 4H).
EXAMPLE 133
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-benzyl-1,2,3,4-
tetrahydroisoquinolinyl)pyridinecarboxylic acid
EXAMPLE 133A
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1,2,3,4-
tetrahydroisoquinolinyl)picolinate
The title compound was prepared by substituting 6-bromo-1,2,3,4-
tetrahydroisoquinoline hydrochloride for EXAMPLE 75A in EXAMPLE 75B.
EXAMPLE 133B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(2-
benzyl-1,2,3,4-tetrahydroisoquinolinyl)picolinate
A suspension of EXAMPLE 133A (20 mg) , benzaldehyde (6.58 μL), MP-CNBH3
(100 mg, 2.47 mmol/g), acetic acid (2 μL) in dichloromethane (2 mL)/methanol (2 mL) was
shaken at room temperature for 18 hours. The reaction mixture was filtered, washed with
methanol/dichloromethane, concentrated and purified by RP HPLC (C8, 30 - 100%
CH3CN/water/0.1% TFA) to e the title compound.
EXAMPLE 133C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-benzyl-1,2,3,4-
tetrahydroisoquinolinyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 133B for EXAMPLE
1E in EXAMPLE 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.96 (s, 1H), 12.86
(s, 1H), 10.10 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.63 (d, 2H), 7.60 – 7.41 (m, 7H), 7.36 (m,
2H), 7.26 – 7.15 (m, 3H), 6.99 (d, 1H), 4.98 (s, 2H), 4.49 (d, 2H), 4.36 (s, 2H), 3.90 (t, 2H),
3.43 – 3.28 (m, 2H), 3.10 (s, 2H), 3.02 (t, 2H).
EXAMPLE 134
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 134A
methyl cycloheptanecarboxylate
To a solution of 25.0 g cycloheptanecarboxylic acid in methanol (300 mL) was added
concentrated H2SO4 (0.5 g) and the mixture was stirred at reflux overnight. The on
e was concentrated under vacuum and the e was diluted with ethyl ether (500
mL). The mixture was washed with water and brine, dried over Na2SO4, filtered, and
concentrated under reduced re to give the title compound.
EXAMPLE 134B
methyl 1-(2-methoxyethyl)cycloheptanecarboxylate
To a cooled (-78oC) solution of lithium diisopropylamide (2.0M, 6 mL) in
tetrahydrofuran (10 mL) was added EXAMPLE 134A (1.60 g) in ydrofuran (10 mL).
The mixture was stirred at -78oC for 30 minutes and a solution of 1-bromomethoxyethane
(1.73 g) in tetrahydrofuran (10 mL) was added to the mixture. The mixture was stirred
overnight and d to warm up to room temperature. The mixture was quenched with
aqueous NH4Cl, extracted with ethyl acetate (200 mL), washed with water (3 times) and
brine, and dried over Na2SO4. tion and concentration gave the crude product which was
used in the next reaction without further purification.
EXAMPLE 134C
(1-(2-methoxyethyl)cycloheptyl)methanol
A solution of E 134B (2.25 g) in diethyl ether (10 mL) was added dropwise
to a suspension of LiAlH4 (0.40 g) in diethyl ether (20 mL). Once the addition was finished,
the mixture was refluxed for 90 minutes, and cooled to 0oC. Aqueous NaOH (2N, 50 mL)
was added slowly. The mixture was then extracted with ethyl acetate (300 mL) and the
organic layer was washed with brine and dried over Na2SO4. Filtration and concentration
provided the title compound.
EXAMPLE 134D
1-((1-(2-methoxyethyl)cycloheptyl)methyl)-1H-pyrazole
The title compound was prepared by tuting EXAMPLE 134C for (3-
(dimethylamino)phenyl)methanol and 1H-pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole in E 34A.
E 134E
(3-methoxypropyl)cycloheptyl)methyl)methyl-1H-pyrazole
The title compound was ed by substituting EXAMPLE 134D for EXAMPLE
63A in EXAMPLE 63B.
EXAMPLE 134F
4-iodo((1-(2-methoxyethyl)cycloheptyl)methyl)methyl-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 134E for EXAMPLE
65E in EXAMPLE 65F.
EXAMPLE 134G
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 134F for EXAMPLE
75A in EXAMPLE 75B, and then substituting that product for E 8B in EXAMPLE
8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (s, 1H), 8.04 (d, 1H), 7.79 (d,
1H), 7.61 (d, 1H), 7.40 (m, 6H), 6.95 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.83 (s, 2H), 3.41 (t,
2H), 3.20 (s, 3H), 3.01 (t, 2H), 2.11 (s, 3H), 1.43 (m, 16H)
EXAMPLE 135
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(piperidin
ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 78B for EXAMPLE 1E
in EXAMPLE 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 13.06 (s, 1H), 12.86 (s,
1H), 8.45 (d, 1H), 8.15 (d, 1H), 8.04 (d, 1H), 7.80 (d, 2H), 7.70 (d, 1H), 7.62 (d, 1H), 7.57 (d,
1H), 7.52 – 7.45 (m, 1H), 7.45 – 7.30 (m, 3H), 6.95 (d, 1H), 4.95 (s, 2H), 4.05 (d, 2H), 3.87
(t, 2H), 3.25 (d, 2H), 3.00 (t, 2H), 2.84 (dd, 2H), 2.10 (dd, 1H), 1.66 (d, 2H), 1.33 (td, 2H).
EXAMPLE 136
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-(pyridin
ylmethyl)-1,2,3,4-tetrahydroisoquinolinyl]pyridinecarboxylic acid
EXAMPLE 136A
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(2-
(pyridinylmethyl)-1,2,3,4-tetrahydroisoquinolinyl)picolinate
The title compound was prepared by substituting picolinaldehyde for benzaldehyde in
EXAMPLE 133B.
EXAMPLE 136B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-(pyridin
ylmethyl)-1,2,3,4-tetrahydroisoquinolinyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 136A for EXAMPLE
1E in EXAMPLE 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 13.00 (s, 1H), 12.86
(s, 1H), 10.56 (s, 1H), 8.71 (dd, 1H), 8.04 (d, 1H), 7.96 (td, 1H), 7.79 (d, 1H), 7.68 – 7.56 (m,
3H), 7.55 – 7.42 (m, 3H), 7.36 (ddd, 2H), 7.21 (d, 3H), 7.00 (d, 2H), 4.99 (s, 2H), 4.63 (s,
2H), 4.47 (s, 2H), 3.93 – 3.88 (m, 2H), 3.63 – 3.55 (m, 2H), 3.13 (t, 2H), 3.02 (t, 2H).
EXAMPLE 137
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-
hexylmethyl)-1,2,3,4-tetrahydroisoquinolinyl]pyridinecarboxylic acid
EXAMPLE 137A
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)[2-
(cyclohexylmethyl)-1,2,3,4-tetrahydroisoquinolinyl]picolinate
The title nd was prepared by substituting cyclohexanecarbaldehyde for
dehyde in EXAMPLE 133B.
EXAMPLE 137B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-
(cyclohexylmethyl)-1,2,3,4-tetrahydroisoquinolinyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 137A for EXAMPLE
1E in EXAMPLE 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.97 (s, 1H), 12.87
(s, 1H), 9.42 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.67 – 7.59 (m, 2H), 7.52 – 7.42 (m, 2H),
7.36 (ddd, 2H), 7.22 (s, 3H), 7.00 (d, 1H), 4.99 (s, 2H), 4.58 (d, 1H), 4.30 (dd, 1H), 3.91 (t,
2H), 3.55 (d, 2H), 3.40 – 3.25 (m, 2H), 3.18 (s, 1H), 3.12 – 2.98 (m, 4H), 1.96 – 1.55 (m, 6H),
1.32 – 1.12 (m, 2H), 1.09 – 0.89 (m, 2H).
EXAMPLE 138
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-(cyclohexyloxy)-
3'-methyl-3,4'-bipyridinecarboxylic acid
EXAMPLE 138A
2-(cyclohexyloxy)iodomethylpyridine
Cyclohexanol (0.501 g) in ydrofuran (3.5 mL) was treated with NaH (0.1 g)
until gas evolution ceased. 2-Fluoroiodomethylpyridine (0.237 g) in tetrahydrofuran
(1.5 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours and
was quenched with ice-water. The ing mixture was extracted with ethyl acetate. The
ed c layer was washed with brine, dried over Na2SO4, filtered, and concentrated.
The e was purified by preparative TLC, and was eluted with eum ether to provide
the title compound.
EXAMPLE 138B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2'-
(cyclohexyloxy)-3'-methyl-3,4'-bipyridinecarboxylate
The title compound was prepared by substituting EXAMPLE 138A for EXAMPLE
1D and EXAMPLE 30A for EXAMPLE 82D in EXAMPLE 82E.
EXAMPLE 138C
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-(cyclohexyloxy)-
3'-methyl-3,4'-bipyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 138B for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) δ ppm7.86-7.88 (m, 1H),
.74 (m, 1H), 7.23-7.48 (m, 7H), 6.95 (d, 1H), 6.50 (d, 1H), 5.04-5.12 (m, 3H), 3.90-
3.93 (m, 2H), 3.10-3.13 (m, 2H), 1.86-1.90 (m, 2H), 1.85 (s, 3H), 1.66-1.68 (m, 2H), 1.17-
1.50 (m, 6H).
EXAMPLE 139
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-(cyclohexyloxy)-
3,4'-bipyridinecarboxylic acid
EXAMPLE 139A
2-(cyclohexyloxy)iodopyridine
The title compound was prepared by substituting 2-fluoroiodo-pyridine for 2-
fluoroiodomethylpyridine in EXAMPLE 138A.
EXAMPLE 139B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2'-
(cyclohexyloxy)-3,4'-bipyridinecarboxylate
The title compound was prepared by substituting EXAMPLE 139A for EXAMPLE
1D and EXAMPLE 30A for EXAMPLE 82D in EXAMPLE 82E.
EXAMPLE 139C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-(cyclohexyloxy)-
3,4'-bipyridinecarboxylic acid
The title nd was prepared by substituting EXAMPLE 139B for E
8B in EXAMPLE 8C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) δ ppm 12.89 (s, 1H), 8.11
(d, 1H), 8.04 (d, 1H), 7.76 (d, 1H), 7.73 (d, 1H), 7.63 (d, 1H), 7.43-7.49 (m, 2H), 7.34-7.39
(m, 2H), 6.99 (d, 1H), 6.89 (d, 1H), 6.67 (s, 1H), 5.01 (s, 3H), 3.92 (s, 2H), 3.02(s, 2H), 1.95-
1.98 (m, 2H), 1.71-1.78 (m, 2H), 1.54-1.56 (m, 1H), 1.35-1.45 (m, 4H), 1.23-1.30 (m, 1H).
E 140
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-phenoxy-3,4'-
bipyridinecarboxylic acid
EXAMPLE 140A
4-iodophenoxypyridine
Phenol (0.464 g) in N,N-dimethylformamide (5 mL) was treated with sodium hydride
(60% in mineral oil, 0.057 g). After the gas evolution ceased, 2-fluoroiodopyridine (0.22
g) was added slowly to the solution. The mixture was heated at 100°C overnight under
nitrogen atmosphere, cooled, diluted with ethyl acetate and washed with aqueous NaOH. The
organic layer was concentrated and purified by preparative TLC, eluting with petroleum
ether/ethyl acetate (10/1).
EXAMPLE 140B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2'-
phenoxy-3,4'-bipyridinecarboxylate
The title compound was prepared by substituting EXAMPLE 140A for EXAMPLE
1D and EXAMPLE 30A for EXAMPLE 82D in EXAMPLE 82E.
EXAMPLE 140C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-phenoxy-3,4'-
bipyridinecarboxylic acid
The title compound was ed by substituting E 140B for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) δ ppm 12.89 (s, 1H), 8.03-
8.12 (m, 2H), 7.78 (t, 2H), 7.63 (d, 1H), 7.34-7.49 (m, 6H), 7.18-7.22 (m, 1H), , 2H),
7.08 (d, 1H), 7.03 (d, 1H), 6.96 (s, 1H), 4.95-5.06 (m, 2H), 3.93 (t, 2H), .04 (m, 2H).
EXAMPLE 141
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H-
pyrrolo[2,3-b]pyridinyl)pyridinecarboxylic acid
EXAMPLE 141A
1-benzylbromo-1H-pyrrolo[2,3-b]pyridine
To a solution of 3-bromo-1H-pyrrolo[2,3-b]pyridine (500 mg) in N,N-
dimethylformamide (10 mL) was added NaH (70 mg). The mixture was stirred for 50
minutes, and (bromomethyl)benzene (0.290 mL) was added dropwise. The reaction was
d for 48 hours and quenched by the addition of water and ethyl acetate. The layers were
separated, and the organic layer was washed with brine, dried with Na2SO4, filtered and
concentrated. The e was purified by silica gel chromatography, g with 2:1 hexane
to ethyl e, to give the titlecompound.
EXAMPLE 141B
1-benzyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrrolo[2,3-b]pyridine
The title compound was prepared by substituting EXAMPLE 141A for EXAMPLE
84C in EXAMPLE 84D.
EXAMPLE 141C
utyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)
(1-benzyl-1H-pyrrolo[2,3-b]pyridinyl)picolinate
The title compound was prepared by substituting EXAMPLE 141B for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 141D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H-
pyrrolo[2,3-b]pyridinyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 141C for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (v br s, 1H),
8.28 (s, 1H), 8.03 (d, 1H), 7.87 (d, 1H), 7.80 (d, 1H), 7.75 (d, 1H), 7.63 (d, 1H), 7.62 (s, 1H),
7.46 (m,2H), 7.40-7.20 (m, 7H), 7.12 (m, 1H), 6.99 (d, 1H), 5.51 (s, 2H), 4.99 (s, 2H), 3.92
(br t, 2H), 3.03 (br t, 2H).
EXAMPLE 142
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-2'-
phenoxy-3,4'-bipyridinecarboxylic acid
EXAMPLE 142A
4-iodomethylphenoxypyridine
The title compound was prepared by substituting phenol for cyclohexanol in
EXAMPLE 138A.
EXAMPLE 142B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3'-methyl-
2'-phenoxy-3,4'-bipyridinecarboxylate
The title compound was prepared by substituting EXAMPLE 142A for EXAMPLE
1D and EXAMPLE 30A for EXAMPLE 82D in EXAMPLE 82E.
EXAMPLE 142C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-2'-
y-3,4'-bipyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 142B for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (400 MHz, ylsulfoxide-d 6) δ ppm 7.88 (d, 1H), 7.72
(s, 1H), 7.47 (d, 1H), 7.38 (d, 1H), 7.28-7.32 (m, 4H), 7.24-7.28 (m, 3H), 7.05-7.10 (m, 3H),
6.97 (d, 1H), 6.67 (d, 1H),5.09-5.13 (m, 2H), 3.84 (s, 2H), 3.04 (s, 2H), 2.01 (s, 3H).
EXAMPLE 143
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-2'-
[methyl(phenyl)amino]-3,4'-bipyridinecarboxylic acid
EXAMPLE 143A
4-iodo-N,3-dimethyl-N-phenylpyridinamine
2-Fluoroiodomethylpyridine (700 mg) in N-methylaniline (2.5 mL) was heated
at 180ºC in a Biotage Initiator microwave reactor for 18 hours. The reaction mixture was
loaded onto a silica gel cartridge, and was eluted with 0 - 100% dichloromethane in hexanes
to provide the title compound.
E 143B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3'-methyl-
thyl(phenyl)amino)-3,4'-bipyridinecarboxylate
The title compound was prepared by substituting EXAMPLE 143A for EXAMPLE
1D and EXAMPLE 30A for EXAMPLE 82D in EXAMPLE 82E.
EXAMPLE 143C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-2'-
[methyl(phenyl)amino]-3,4'-bipyridinecarboxylic acid
The title compound was ed by substituting EXAMPLE 143B for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (400 MHz, DMSO-d 6) δ ppm 8.24 (d, 1H), 7.76 (d, 1H),
7.49 , 7.32-7.41 (m, 4H), 7.19-7.29 (m, 3H), 7.13-7.15 (m, 2H), 6.96 (d, 1H), 6.71-
6.77 (m, 4H), 5.07-5.13 (m, 2H), 3.80-3.83 (m, 2H), 3.37 (s, 3H), 3.05 (t, 2H), 1.64 (s, 3H).
EXAMPLE 144
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(methoxymethyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 144A
methyl 1-(methoxymethyl)cyclohexanecarboxylate
The title compound was prepared by tuting bromomethylmethyl ether for 1-
bromomethoxyethane and methyl cyclohexanecarboxylate for EXAMPLE 134A in
EXAMPLE 134B.
EXAMPLE 144B
(1-(methoxymethyl)cyclohexyl)methanol
The title compound was prepared by tuting EXAMPLE 144A for EXAMPLE
134B in EXAMPLE 134C.
EXAMPLE 144C
(methoxymethyl)cyclohexyl)methyl)-1H-pyrazole
The title compound was prepared by tuting EXAMPLE 144B for (3-
(dimethylamino)phenyl)methanol and 1H-pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 144D
1-((1-(methoxymethyl)cyclohexyl)methyl)methyl-1H-pyrazole
The title compound was prepared by tuting EXAMPLE 144C for EXAMPLE
63A in EXAMPLE 63B.
EXAMPLE 144E
4-iodo((1-(methoxymethyl)cyclohexyl)methyl)methyl-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 144D for EXAMPLE
65E in EXAMPLE 65F.
EXAMPLE 144F
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-
(methoxymethyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 144E for EXAMPLE
75A in EXAMPLE 75B, and then tuting that product for EXAMPLE 8B in EXAMPLE
8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 1H), 8.04 (d, 1H), 7.54 (m,
8H), 6.94 (d, 1H), 4.94 (s, 2H), 3.86 (t, 2H), 3.28 (m, 4H), 3.03 (m, 4H), 1.23 (m, 10H).
EXAMPLE 145
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3,3-
dimethyl(morpholinyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid
EXAMPLE 145A
1-amino-3,3-dimethylcyclohexanecarbonitrile
To a solution of 3,3-dimethylcyclohexanone (1.89 g) in water (3.8 mL) and ethanol
(4.5 mL) was added ammonium chloride (920 mg), followed by concentrated ammonium
hydroxide solution (2 mL) and trimethylsilanecarbonitrile (1.71 g). The reaction was heated
to 70 °C for 18 hours. The on was concentrated to dryness, and was partitioned between
water and methylene chloride. The layers were separated, and the aqueous layer was
extracted with additional methylene chloride (3 x 25 mL). The combined organic layers were
dried over MgSO4, filtered and concentrated. The residue was purified by silica gel
chromatography, eluting with 40% ethyl acetate in eum ether, to give the title
compound.
EXAMPLE 145B
1-amino-3,3-dimethylcyclohexanecarboxamide
A solution of EXAMPLE 145A (4.6 g) in concentrated H2SO4 (9 mL) was heated to
70 °C for 20 minutes. The reaction mixture was cooled to about 0 °C in an ice bath and
diluted with water. The pH of the solution was adjusted to pH 7-8 by addition of
concentrated aqueous ammonia solution. The aqueous layer was extracted with methylene
chloride (2 x 50 mL). The combined organic layers were washed with water (1 x 20 mL),
dried over MgSO4, filtered, and concentrated to give the title compound, which was used in
the next step without further purification.
E 145C
ethyl 1-amino-3,3-dimethylcyclohexanecarboxylate
To a solution of EXAMPLE 145B (3.8 g) in water (25 mL) was added concentrated
hydrochloric acid (25 mL). The reaction mixture was heated to 110 °C for 3 hours, and then
evaporated to dryness. The residue (3.5 g) was ved in l (30 mL), and sulfurous
dichloride (10 g) was added. The resulting mixture was heated to 80 °C for about 18 hours,
after which it was concentrated to dryness. The residue was diluted with saturated aqueous
NaHCO3 on and extracted with methylene chloride (2 x 25 mL). The organic layer was
dried over MgSO4, filtered and concentrated. The residue was purified by silica gel
chromatography, eluting with 2:1 eum ethyl acetate, to give the title compound.
EXAMPLE 145D
ethyl 3,3-dimethylmorpholinocyclohexanecarboxylate
To a solution of EXAMPLE 145C (3.5 g) in N,N-dimethylformamide (30 mL) was
added o(2-bromoethoxy)ethane (5.8 g) and K2CO3 (6.5 g). The reaction mixture
was heated to 95 °C for 18 hours. The mixture was cooled to room temperature, diluted with
water, and extracted with methylene chloride (3 x 50 mL). The combined organic layers were
washed with saturated NaCl solution (1 x 25 mL), dried over Na2SO4, filtered, and
concentrated. The e was purified by silica gel chromatography, eluting with 4:1
eum ether/ethyl acetate solution, to give the title compound.
EXAMPLE 145E
(3,3-dimethylmorpholinocyclohexyl)methanol
To a cooled (0 °C) solution of EXAMPLE 145D (3.7 g) in tetrahydrofuran (20 mL)
was added lithium aluminum hydride (720 mg). The cooling bath was d, and the
reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched by
the sequential addition of water (0.8 mL) and 15% aqueous NaOH solution (2 mL). The
mixture was dried with MgSO4, filtered and concentrated to give the title compound, which
was used in the subsequent step t further purification.
EXAMPLE 145F
4-(1-((1H-pyrazolyl)methyl)-3,3-dimethylcyclohexyl)morpholine
The title compound was prepared by substituting EXAMPLE 145E for (3-
(dimethylamino)phenyl)methanol and 1H-pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 145G
4-(1-((4-bromomethyl-1H-pyrazolyl)methyl)-3,3-dimethylcyclohexyl)morpholine
A solution of EXAMPLE 145F (0.53 g) in tetrahydrofuran (15 mL) was cooled to 0
°C, and nBuLi (0.917 ml) was added dropwise. The reaction was d at 0 °C for 30
minutes, and iodomethane (0.155 mL) was added. The cooling bath was removed, and the
on mixture was warmed to room temperature. The reaction e was diluted with
methylene chloride (50 mL) and washed with water (2 x 25 mL). The c layer was dried
over magnesium sulfate, filtered, and concentrated. The residue was dissolved in N,N-
dimethylformamide (10 mL) and treated with N-bromosuccinimide(0.136 g). After 1 hour,
the reaction e was diluted with methylene chloride (50 mL) and washed with water (2 x
mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The
residue was purified by silica gel chromatography, eluting with a gradient of 0 to 75% ethyl
acetate in hexanes, to give the title nd.
EXAMPLE 145H
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3,3-
dimethyl(morpholinyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid
A e of EXAMPLE 30A (0.192 g), EXAMPLE 145G (0.083 g), 1,3,5,7-
tetramethyltetradecane-2,4,8-trioxaphosphaadamantane (9.25 mg), potassium phosphate
(0.167 g) and ), and tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.012 g)
was dissolved in ydrofuran (2 mL) and water (0.66 mL). The reaction mixture was
flushed with nitrogen and then heated under microwave conditions ge) to 140 °C for 5
minutes. The reaction was diluted with ethyl e (50 mL), washed with water (25 mL)
and brine (25 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was
purified by silica gel chromatography, eluting with a gradient of 5% to 100% ethyl acetate in
hexane, to give the intermediate ester. The residue was dissolved in methylene de (0.5
mL) and treated with TFA (0.5 mL). The reaction mixture was stirred overnight and
concentrated to dryness. The residue was purified by RP-HPLC, eluting with 10% to 70%
itrile in water ning 0.1% v/v TFA, to give the title compound. 1H NMR (300
MHz, ylsulfoxide-d6) δ 12.85 (s, 1H), 9.54 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d,
1H), 7.58 – 7.41 (m, 4H), 7.41 – 7.30 (m, 2H), 6.98 (d, 1H), 4.97 (s, 3H), 4.57 (s, 6H), 4.02
(s, 1H), 3.90 (t, 2H), 3.81 – 3.31 (m, 3H), 3.02 (t, 2H), 2.73 (s, 1H), 2.20 (s, 2H), 2.01 – 1.39
(m, 4H), 1.33 – 0.70 (m, 6H).
EXAMPLE 146
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)-3,3-dimethylcyclohexyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid
EXAMPLE 146A
2-(3,3-dimethylcyclohexylidene)-1,3-dithiane
To a solution of (1,3-dithianyl)trimethylsilane (5.0 g) in tetrahydrofuran at -78°C
was added n-butyllithium (1.6M, 16.24 mL). After ng for 30 minutes, 3,3-
dimethylcyclohexanone (3.3 g) was added as a solution in tetrahydrofuran and the reaction
mixture was allowed to warm to room temperature. The reaction mixture was diluted with
diethyl ether (100 mL), washed with water (50 mL) and brine (50 mL), dried over magnesium
sulfate, filtered, and concentrated. Silica gel chromatography g with a nt of
0.13% to 2.5% hexanes gave the title compound.
EXAMPLE 146B
methyl 3,3-dimethylcyclohexanecarboxylate
EXAMPLE 146A (2.00 g) and copper(II) sulfate pentahydrate (6.56 g) in methanol
(25 mL) were heated to 65°C and stirred overnight. The reaction mixture was ed, rinsed
with ether and concentrated. The residue was loaded onto silica gel and eluted using a
gradient of 2% to 20% ethyl acetate/hexanes to give the title compound.
EXAMPLE 146C
methyl 1-(2-methoxyethyl)-3,3-dimethylcyclohexanecarboxylate
A solution of EXAMPLE 146B (0.60 g) in tetrahydrofuran (5 mL) was added to
lithium diisopropylamide (2.0 M, 2.10 mL) at -78°C. After stirring for 30 minutes, 1-bromo-
2-methoxyethane (0.64 g) was added and the reaction mixture was allowed to warm to room
temperature. The reaction mixture was diluted with ether (75 mL), washed with water (50
mL) and brine (50 mL), dried over magnesium sulfate, filtered, and trated. Silica gel
chromatography eluting with 1-20% ethyl acetate in hexanes provided the title compound.
EXAMPLE 146D
1-((1-(2-methoxyethyl)-3,3-dimethylcyclohexyl)methyl)-1H-pyrazole
To a solution of EXAMPLE 146C (0.37 g) in diethyl ether (5 mL) was added LiAlH4
(1.0M, 1.61 mL) dropwise. The reaction was stirred for 2 hours at room temperature. The
reaction mixture was cooled to 0°C, quenched with water (0.062 mL), 15% aqueous NaOH
(0.062 mL), and then more water (0.17 mL) was added. The on mixture was stirred for
1 hour, magnesium sulfate was added, and the mixture was filtered and concentrated. The
e was dissolved in toluene (5 mL), 1H-pyrazole (0.17 g) and
cyanomethylenetributylphosphorane (0.47 g) were added and the mixture was heated to 85°C
overnight. The reaction e was cooled, loaded onto silica gel and eluted with 1-10%
ethyl acetate in hexanes to give the title compound.
EXAMPLE 146E
1-((1-(2-methoxyethyl)-3,3-dimethylcyclohexyl)methyl)methyl-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 146D for EXAMPLE
63A in EXAMPLE 63B.
EXAMPLE 146F
4-iodo((1-(2-methoxyethyl)-3,3-dimethylcyclohexyl)methyl)methyl-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 146E for EXAMPLE
66B in EXAMPLE 66C.
EXAMPLE 146G
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((1-(2-
yethyl)-3,3-dimethylcyclohexyl)methyl)methyl-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 146F for EXAMPLE
77D in EXAMPLE 77E.
EXAMPLE 146H
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethyl)-3,3-dimethylcyclohexyl]methyl}methyl-1H-pyrazolyl)pyridine
ylic acid
The title nd was prepared by substituting EXAMPLE 146G for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (300 MHz, ylsulfoxide-d 6) δ 12.85 (s, 1H), 8.04 (d,
1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.48 (dd, 2H), 7.46 -7.41 (m, 1H), 7.36 (ddd, 2H), 7.29 (s,
1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.96 -3.73 (m, 4H), 3.20 (s, 3H), 3.00 (dd, 2H), 2.10 (s, 3H),
1.77-1.39 (m, 4H), 1.36 -0.99 (m, 8H), 0.93 (d, 6H).
EXAMPLE 147
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(3-
methoxypropyl)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 147A
methyl 1-(3-methoxypropyl)cycloheptanecarboxylate
The title compound was prepared by substituting 1-bromomethoxypropane for 1-
bromomethoxyethane in EXAMPLE 134B.
EXAMPLE 147B
(1-(3-methoxypropyl)cycloheptyl)methanol
The title compound was prepared by substituting EXAMPLE 147A for EXAMPLE
134B in EXAMPLE 134C.
EXAMPLE 147C
1-((1-(3-methoxypropyl)cycloheptyl)methyl)-1H-pyrazole
The title compound was ed by substituting EXAMPLE 147B for (3-
(dimethylamino)phenyl)methanol and 1H-pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 147D
1-((1-(3-methoxypropyl)cycloheptyl)methyl)methyl-1H-pyrazole
The title compound was prepared by substituting E 147C for EXAMPLE
63A in EXAMPLE 63B.
EXAMPLE 147E
4-iodo((1-(3-methoxypropyl)cycloheptyl)methyl)methyl-1H-pyrazole
The title compound was prepared by substituting E 147D for EXAMPLE
65E in EXAMPLE 65F.
EXAMPLE 147F
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(3-
methoxypropyl)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 147E for EXAMPLE
75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 8B in EXAMPLE
8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 1H), 8.04 (d, 1H), 7.79 (d,
1H), 7.61 (d, 1H), 7.40 (m, 5H), 7.27 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.80 (s, 3H), 3.27 (t,
2H), 3.21 (s, 3H), 3.01 (t, 2H), 2.11 (s, 3H), 1.39 (m, 18H).
EXAMPLE 148
N-(1,3-benzothiazolyl){5-(1-{[1-(2-methoxyethyl)cycloheptyl]methyl}methyl-1H-
pyrazolyl)[(methylsulfonyl)carbamoyl]pyridinyl}-1,2,3,4-tetrahydroisoquinoline
amide
To a solution of E 134G (50 mg) in dichloromethane (2 mL) was added
methanesulfonamide (7.4 mg), 1-ethyl[3-(dimethylamino)propyl]-carbodiimide
hloride (28 mg) and 4-dimethylaminopyridine (18 mg). The mixture was stirred
overnight. The mixture was loaded on a silica gel column and eluted with 5% methanol in
dichloromethane to give the pure product. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm
8.03 (d, 1H), 7.79 (d, 1H), 7.60 (s, 1H), 7.41 (m, 5H), 7.30 (s, 1H), 7.00 (d, 1H), 4.96 (s, 2H),
3.94 (m, 2H), 3.83 (s, 2H), 3.42 (t, 2H), 3.41 (s, 3H), 3.27 (s, 3H), 3.21 (m, 3H), 3.11 (m, 2H),
2.12 (s, 3H), 1.45 (m, 16H)
EXAMPLE 149
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(tetrahydro-
2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 149A
1-((tetrahydro-2H-pyranyl)methyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
The title compound was prepared by substituting (tetrahydro-2H-pyranyl)methanol
for (3-(dimethylamino)phenyl)methanol in EXAMPLE 34A.
EXAMPLE 149B
utyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
((tetrahydro-2H-pyranyl)methyl)-1H-pyrazolyl)picolinate
The title compound was prepared by tuting EXAMPLE 149A for EXAMPLE
82D in EXAMPLE 82E.
E 149C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(tetrahydro-
2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 149B for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (300 MHz, ylsulfoxide-d 6) G ppm 12.96 -13.25 (m,
1H), 12.85 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.76 (s, 1H), 7.71 (d, 1H), 7.61 (d, 1H), 7.53 (s,
1H), 7.32 -7.51 (m, 4H), 6.94 (d, 1H), 4.94 (s, 2H), 4.08 (d, 2H), 3.80 -3.90 (m, 3H), 3.58 -
3.67 (m, 1H), 3.24 -3.34 (m, 1H), 3.00 (t, 2H), 1.73 -1.80 (m, 1H), 1.49 -1.57 (m, 1H), 1.36
-1.49 (m, 3H), 1.09 -1.24 (m, 1H).
EXAMPLE 150
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
{[(1R,2R,3R,5S)(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]heptyl]methyl}-1H-
pyrazolyl)pyridinecarboxylic acid
EXAMPLE 150A
(1R,2R,3R,5S)(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]heptanecarbaldehyde
To a solution of (1S,5R)(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]heptene
(940 mg) in tetrahydrofuran (5 mL) was added dropwise 9-borabicyclo[3.3.1]nonane (0.5 M
in tetrahydrofuran, 10.43 mL). The reaction mixture was heated to reflux overnight, then
cooled to -35 oC and then placed under a CO atmosphere (1 atm). LiAl(OtBu)3H (1M in
tetrahydrofuran, 5.21 mL) was added dropwise over 30 minutes. Following the addition, the
reaction mixture was stirred for 1.5 hours under CO (1 atm), during which time the reaction
temperature was increased to 0oC. The mixture was warmed to room temperature and d
for 45 minutes, then the system was d with argon and a buffer solution (5.28 g
NaH2PO4 and 6.86 g K2HPO4 in 20 mL water) was added. The flask was chilled in a -10 oC
cooling bath and the reaction was quenched by dropwise addition of 30% aqueous H2O2
solution (2.2 mL), then warmed to room temperature and stirred for 15 s. The reaction
mixture was partitioned between water (50 mL) and ethyl acetate (3 x 75 mL). The organic
phase was then washed with 10% 3 (3 x 50 mL) and brine (50 mL), then dried
(MgSO4), filtered, and concentrated. The crude product was purified by flash
chromatography on silica gel eluting with 0 to 50% ethyl acetate in hexanes to give the title
compound.
EXAMPLE 150B
R,3R,5S)(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]heptanyl)methanol
To a solution of EXAMPLE 150A (407 mg) in tetrahydrofuran (10 mL), which was
cooled in a room temperature water bath, was added dropwise LAH (1.0M in tetrahydrofuran,
2.3 mL). The reaction was stirred at room temperature for 1 hour then ed with water
(25 mL). The resulting suspension was filtered through diatomaceous earth, and the filter
cake was rinsed with ether (50 mL). The layers were separated and the aqueous layer was
extracted with ether (2 x 25 mL). The extracts were washed with brine (25 mL), dried
(MgSO4), filtered, and concentrated to give the title compound, which was used without
further purification.
EXAMPLE 150C
1-(((1R,2R,3R,5S)(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]heptanyl)methyl)
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was ed by substituting EXAMPLE 150B for (3-
(dimethylamino)phenyl)methanol in EXAMPLE 34A.
EXAMPLE 150D
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)
1R,2R,3R,5S)(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]heptanyl)methyl)-1H-
pyrazolyl)picolinate
The title nd was prepared by substituting EXAMPLE 150C for EXAMPLE
82D in EXAMPLE 82E.
EXAMPLE 150E
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-
{[(1R,2R,3R,5S)(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]heptyl]methyl}-1H-
pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 150D for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (300 MHz, DMSO-d 6) G ppm 12.89 -13.24 (m, 1H), 12.85
(s, 1H), 8.04 (d, 1H), 7.87 (s, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.61 (d, 1H), 7.54 (s, 1H), 7.45 -
7.51 (m, 1H), 7.40 - 7.45 (m, 1H), 7.32 - 7.39 (m, 2H), 6.95 (d, 1H), 4.94 (s, 2H), 3.90 - 4.10
(m, 2H), 3.87 (t, 2H), 3.20 - 3.31 (m, 2H), 3.15 (s, 3H), 3.00 (t, 2H), 2.19 - 2.31 (m, 2H), 1.81
- 1.93 (m, 3H), 1.71 - 1.80 (m, 1H), 1.47 - 1.63 (m, 2H), 1.31 - 1.44 (m, 1H), 1.16 (s, 3H),
0.94 (s, 3H), 0.75 (d, 1H).
EXAMPLE 151
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 151A
1-oxaspiro[2.6]nonane
To a e of trimethylsulfonium iodide (35.7 g) in 300 mL dry DMSO was added
11.2 g of cycloheptanone with stirring. A solution of potassium tert-butoxide (16.83 g) in 200
mL dry DMSO was slowly added. The resulting solution was stirred at room ature for
16 hours. The reaction mixture was ed by addition of water (600 mL), and extracted
with diethyl ether (3 × 200 mL). The ed organic layers were washed with water (200
mL), dried over Na2SO4, filtered, and concentrated under reduced re to give the
product.
EXAMPLE 151B
1-((4-iodomethyl-1H-pyrazolyl)methyl)cycloheptanol
The title compound was prepared by substituting EXAMPLE 151A for EXAMPLE
141A in EXAMPLE 141B.
E 151C
4-iodo((1-(2-methoxyethoxy)cycloheptyl)methyl)methyl-1H-pyrazole
To a solution of EXAMPLE 151B (356 mg) in N,N-dimethylacetamide (6 mL) was
added NaH (128 mg, 60% in mineral oil). The mixture was stirred for 30 minutes. Then, 1-
bromomethoxyethane (740 mg) was added to the mixture, which was stirred overnight.
The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water, brine
and dried over Na2SO4. After filtration and concentration, the residue containing the crude
title compound was used in the next reaction without further purification.
EXAMPLE 151D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by tuting EXAMPLE 151C for EXAMPLE
75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 8B in EXAMPLE
8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (s, 1H), 8.03 (d, 1H), 7.79 (d,
1H), 7.61 (d, 1H), 7.41 (m, 5H), 7.27 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 4.03 (s, 2H), 3.89 (t,
2H), 3.39 (t, 2H), 3.21 (m, 3H), 3.01 (t, 2H), 2.13 (s, 3H), 1.43 (m, 14H).
EXAMPLE 152
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[1-cyclohexyl-
3-(morpholinyl)propyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 152A
3-cyclohexyl(1H-pyrazolyl)propanal
A solution of cyclohexylacrylaldehyde (4.94 g ) (made according to Organic
Letters (2011), 13(1), 70-73), 2-(bis(3,5-bis(trifluoromethyl)phenyl)-
(trimethylsilyloxy)methyl)pyrrolidine (0.712 g ) and 4-nitrobenzoic acid (0.124 mL) in
toluene (60 mL) was stirred at room temperature for 10 minutes and1H-pyrazole (1.622 g)
was added. The reaction mixture was stirred for 3 days, and purified by flash
chromotography (silica gel, 0 - 50% ethyl acetate/hexanes).
EXAMPLE 152B
4-(3-cyclohexyl(1H-pyrazolyl)propyl)morpholine
The title compound was prepared by substituting EXAMPLE 152A for dehyde
and morpholine for EXAMPLE 133A in EXAMPLE 133B.
EXAMPLE 152C
4-(3-cyclohexyl(5-methyl-1H-pyrazolyl)propyl)morpholine
The title compound was prepared by substituting EXAMPLE 152B for EXAMPLE
63A in EXAMPLE 63B.
EXAMPLE 152D
4-(3-(4-bromomethyl-1H-pyrazolyl)cyclohexylpropyl)morpholine
The title compound was prepared by substituting EXAMPLE 152C for EXAMPLE
63B in EXAMPLE 63C.
E 152E
utyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(1-
cyclohexylmorpholinopropyl)methyl-1H-pyrazolyl)picolinate
The title nd was prepared by substituting EXAMPLE 152D for EXAMPLE
77D in EXAMPLE 77E.
EXAMPLE 152F
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[1-cyclohexyl-
3-(morpholinyl)propyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting E 152E for EXAMPLE
1E in EXAMPLE 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.86 (s, 1H), 9.63
(s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.53 – 7.42 (m, 3H), 7.36 (dd, 3H), 6.97 (d,
1H), 6.51 (s, 1H), 4.97 (s, 2H), 4.00 – 3.85 (m, 5H), 3.58 (t, 2H), 3.02 (t, 2H), 2.31 – 2.18 (m,
2H), 1.93 – 1.69 (m, 4H), 1.60 (d, 2H), 1.28 – 0.79 (m, 8H).
E 153
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H-
indazolyl)pyridinecarboxylic acid
EXAMPLE 153A
1-benzyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-indazole
The title compound was prepared by tuting 5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-indazole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazole and benzyl bromide for EXAMPLE 4A in EXAMPLE 4B.
E 153B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)
(1-benzyl-1H-indazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 153A for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 153C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H-
indazolyl)pyridinecarboxylic acid
The title compound was prepared by tuting EXAMPLE 153B for EXAMPLE
1E in EXAMPLE 1F. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (v br s, 1H),
8.12 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.69 (m, 3H), 7.62 (d, 1H), 7.46 (m, 2H), 7.39-7.20
(m, 8H), 6.99 (d, 1H), 5.66 (s, 2H), 4.99 (s, 2H), 3.91 (br t, 2H), 3.02 (br t, 2H).
EXAMPLE 154
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl
(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 154A
4-bromo((tetrahydro-2H-pyranyl)methyl)-1H-pyrazole
The title compound was prepared by tuting hydro-2H-pyranyl)methanol
for (3-(dimethylamino)phenyl)methanol and 4-bromo-1H-pyrazole for 4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 154B
4-bromo((tetrahydro-2H-pyranyl)methyl)-1H-pyrazole
A solution of EXAMPLE 154A (0.25 g) in tetrahydrofuran (2 mL) was cooled to -78
°C and treated with lithium diisopropylamide (prepared from diisopropylamine (0.12 g) and
n-butyllithium (0.77 mL, 1.6 M). After stirring for 1 hour, methyl iodide (0.19 mL) was
added and the reaction mixture was allowed to warm to room temperature. The reaction was
diluted with ether (100 mL) and washed with water (3 x 75 mL) and brine (75 mL), dried over
magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a
gradient of 5% to 30% ethyl acetate/hexanes provided the title compound.
EXAMPLE 154C
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(5-
methyl((tetrahydro-2H-pyranyl)methyl)-1H-pyrazolyl)picolinate
The title nd was prepared by substituting EXAMPLE 154B for EXAMPLE
77D in EXAMPLE 77E.
EXAMPLE 154D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl
(tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 154C for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.85 (s, 2H), 8.04
(d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.52 – 7.41 (m, 3H), 7.36 (m, 2H), 7.28 (s, 1H), 6.95 (d,
1H), 4.95 (s, 2H), 4.15 – 3.76 (m, 5H), 3.73 – 3.55 (m, 1H), 3.27 (m, 1H), 3.01 (t, 2H), 2.12
(s, 3H), 1.77 (m, 1H), 1.60 – 1.33 (m, 4H), 1.24 (m, 1H).
EXAMPLE 155
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl({1-
rpholinyl)propoxy]cycloheptyl}methyl)-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 155A
1-((1-(allyloxy)cycloheptyl)methyl)iodomethyl-1H-pyrazole
The title compound was prepared by substituting 3-bromopropene for o
methoxyethane in EXAMPLE 151C.
E 155B
3-(1-((4-iodomethyl-1H-pyrazolyl)methyl)cycloheptyloxy)propanol
To a solution of E 155A (1.7 g) in tetrahydrofuran (20 mL) was added a 0.5
M 9-borabicyclo[3.3.1]nonane-tetrahydrofuran solution (50 mL, 0.5 M) at 0oC. After the
reaction mixture was stirred for 24 hours at room temperature, a 0.5 M NaOH aqueous
solution (30 mL) and 30% H2O2 aqueous solution (5.5 mL) were added. After the reaction
mixture was stirred for 16 hours, the reaction was then quenched by adding water (15 mL).
The reaction mixture was ted with ethyl acetate, and the organic layer was washed with
water and a saturated aqueous NaCl solution. After the organic layer was dried over Na2SO4,
and filtered, the solvent was evaporated under d pressure. The crude product was
purified on a silica gel column, eluting with 10-50% ethyl acetate in hexanes, to provide the
title compound.
EXAMPLE 155C
3-(1-((4-iodomethyl-1H-pyrazolyl)methyl)cycloheptyloxy)propanal
To a solution of E 155B (393 mg) in dichloromethane (20 mL) was added
Dess-Martin Periodinane (425 mg). After the reaction mixture was d for 4 hours at room
temperature, 2N NaOH aqueous solution (10 mL) was added and the reaction mixture was
extracted with ethyl acetate. The organic layer was washed with water and a saturated NaCl
solution. After the organic layer was dried over Na2SO4 and filtered, the solvent was removed
under reduced pressure. The crude product was used in the next step without further
purification.
E 155D
4-(3-(1-((4-iodomethyl-1H-pyrazolyl)methyl)cycloheptyloxy)propyl)morpholine
To a solution of EXAMPLE 155C (393 mg) in dichloromethane (20 mL) was added
morpholine (263 mg) and sodium triacetoxyborohydride (427 mg). After the reaction mixture
was d overnight at room temperature, 2N NaOH aqueous solution (10 mL) was added
and the reaction mixture was ted with ethyl acetate, and the organic layer was washed
with water and a saturated NaCl solution. After the organic layer was dried over Na2SO4, it
was filtered and the solvent was evaporated under reduced pressure. The crude product was
used in the next reaction without further purification.
EXAMPLE 155E
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl({1-
[3-(morpholinyl)propoxy]cycloheptyl}methyl)-1H-pyrazolyl]pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 155D for EXAMPLE
75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 8B in EXAMPLE
8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 1H), 9.28 (m, 1H), 8.03 (d,
1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.41 (m, 5H), 6.96 (d, 1H), 4.97 (m, 2H), 3.99 (m, 5H), 3.09
(m, 6H), 2.15 (m, 3H), 1.91 (s, 2H), 1.53 (m, 14H).
E 156
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-methyl
[methyl(phenyl)amino]phenyl}pyridinecarboxylic acid
EXAMPLE 156A
(3-bromomethyl-phenyl)-methyl-phenyl-amine
1,3-Dibromomethylbenzene (5.01 g) and N-methylaniline (1.00 g) were added to
toluene (65 mL). The solution was degassed and flushed with nitrogen three times. Cesium
carbonate (9.12 g), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.872 g), and palladium (II)
e (0.314 g) were added. The solution was degassed and flushed with nitrogen and then
heated to 85 oC for 72 hours. The solution was cooled, added to 1 M aqueous HCl, and
extracted with l ether. The extract was washed with brine, dried on anhydrous sodium
e, filtered, and concentrated under . The crude material was ed on silica
gel using 2% ethyl acetate in hexanes.
EXAMPLE 156B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-methyl
[methyl(phenyl)amino]phenyl}pyridinecarboxylic acid tert-butyl ester
The title nd was prepared by substituting EXAMPLE 156A for EXAMPLE
112A in EXAMPLE 112B.
EXAMPLE 156C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-methyl
[methyl(phenyl)amino]phenyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 156B for EXAMPLE
7D in EXAMPLE 7E. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.84 (bs, 1H), 8.04
(d, 1H), 7.79 (d, 1H), 7.65-7.57 (m, 1H), 7.55-7.23 (m, 8H), 7.11 (m, 2H), 6.99 (m, 2H), 6.63
(t, 1H), 6.49 (d, 1H), 4.99 (bs, 2H), 3.93 (t, 2H), 3.18 (s, 3H), 3.03 (t, 2H), 1.80 (s, 3H).
EXAMPLE 157
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-methoxy-
3,3-dimethylcyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 157A
3,3-dimethyl((5-methyl-1H-pyrazolyl)methyl)cyclohexanol
A solution of n-butyllithium (2.5 M, 12.48 mL) in ydrofuran (40 mL) was
cooled to -78°C and a solution of 1,5-dimethyl-1H-pyrazole (3.00 g) in ydrofuran (3
mL) was added se. After ng for 1 hour, a solution of 3,3-dimethylcyclohexanone
(3.94 g) in tetrahydrofuran (3 mL) was added dropwise and the reaction allowed to warm to
0°C. After stirring for 1 hour, the reaction was diluted with ether (100 mL), washed with
water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated.
Silica gel tography eluting with a gradient of 3% to 25% ethyl acetate/hexanes
provided the title compound.
EXAMPLE 157B
1-((4-bromomethyl-1H-pyrazolyl)methyl)-3,3-dimethylcyclohexanol
The title compound was prepared by substituting E 157A for EXAMPLE
63B in EXAMPLE 63C.
EXAMPLE 157C
4-bromo((1-methoxy-3,3-dimethylcyclohexyl)methyl)methyl-1H-pyrazole
A solution of EXAMPLE 157B (0.62 g) was dissolved in N,N-dimethylformamide
(10 mL) and treated with NaH (0.062 g, 60 % in mineral oil). After 10 minutes, iodomethane
(0.16 mL) was added. After 1 hour, additional sodium hydride (0.5 eq.) and iodomethane (0.5
eq.) were added and stirring was continued at room temperature for 3 hours. The reaction was
diluted with ether (75 mL) and washed with water (50 mL) and brine (50 mL), dried over
magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a
gradient of 1.5% to 15% ethyl acetate/hexanes ed the title compound.
EXAMPLE 157D
methoxy-3,3-dimethylcyclohexyl)methyl)methyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 157C for EXAMPLE
84C in EXAMPLE 84D.
EXAMPLE 157E
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-methoxy-
3,3-dimethylcyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid
A solution of a 1:1 ratio of 1,4-dioxane and water was degassed with nitrogen for 45
minutes. This solution (5 mL) was added to EXAMPLE 1D (0.375 g), EXAMPLE 157D
(0.30 g), potassium phosphate (0.62 g), tris(dibenzylideneacetone)dipalladium(0) chloroform
adduct (0.021 g) and 7-tetramethyltetradecane-2,4,8-trioxaphosphaadamantane
(0.034 g), degassed then heated to 90°C under nitrogen for 4 hours. The reaction mixture was
cooled, diluted with ether (75 mL) and washed with water (3 x 50 mL) and brine (50 mL),
dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting
with a gradient of 10% to 50% ethyl acetate/hexanes gave the d ester. The ester was
dissolved in dichloromethane (1 mL) and TFA was added (1 mL) and the mixture was stirred
ght. The reaction mixture was concentrated, loaded onto silica gel and eluted with a
gradient of 0.5% to 4% methanol/dichloromethane to provide the title compound. 1H NMR
(300 MHz, dimethylsulfoxide-d6) δ ppm 12.88 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d,
1H), 7.53 – 7.41 (m, 3H), 7.41 – 7.32 (m, 2H), 7.28 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.98
(s, 2H), 3.89 (t, 2H), 3.15 (s, 3H), 3.01 (t, 2H), 2.12 (s, 3H), 1.77 – 1.00 (m, 8H),0.97 (s, 3H),
0.84 (s, 3H).
EXAMPLE 158
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[(1S,2R,5S)-
6,6-dimethylbicyclo[3.1.1]heptyl]methyl}methyl-1H-1,2,3-triazolyl)pyridine
carboxylic acid
EXAMPLE 158A
(1S,2R,5S)(azidomethyl)-6,6-dimethylbicyclo[3.1.1]heptane
((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptanyl)methanol (500 mg,) was
dissolved in dichloromethane (15 mL). The solution was chilled in an ice bath and
triethylamine (0.633 mL) was added, followed by methanesulfonyl chloride (0.278 mL). The
reaction was stirred for 2 hours at 0 oC, and was transferred to a separatory funnel and washed
with 1N aqueous HCl (15 mL), saturated aqueous NaHCO3 (20 mL) and brine (15 mL), then
dried (Na2SO4), filtered and concentrated to give a crude oil, which was dissolved in N,N-
ylformamide (7.5 mL). Sodium azide (1054 mg) was added and the mixture was
heated to 110oC for 1.5 hours, and was cooled and ioned between water (30 mL) and
ethyl acetate (3 x 25 mL). The organic extracts were washed with brine (25 mL), dried
(Na2SO4), filtered, and concentrated to give a crude oil, which was purified by flash
chromatography on silica gel eluting with 50 to 100% dichloromethane in hexanes to provide
the title compound.
EXAMPLE 158B
1-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptanyl)methyl)methyl(tributylstannyl)-
,3-triazole
E 158A (200 mg), tributyl-n-propynyltin (367 mg) and toluene (1 mL) were
combined in a sealed reaction vessel which was heated to 130oC overnight. The reaction
mixture was placed atop a column and purified by flash chromatography on silica gel eluting
with 0 to 20% ethyl e in hexanes to provide the title compound.
EXAMPLE 158C
methyl 6-aminobromopicolinate
To a on of 6-aminobromopicolinic acid (30 g) in ethyl acetate (300 mL) and
ol (300 mL) was added TMS-diazomethane (70 mL, 2M in hexanes) and the on
mixture was stirred for 3 days. The mixture was concentrated, taken up in ether (500 mL) and
washed with aqueous saturated Na2CO3 solution (twice) and brine, then dried over sodium
sulfate, ed and concentrated to provide the title compound.
EXAMPLE 158D
methyl 3-bromofluoropicolinate
To a solution of nitrosonium terafluoroborate (17.8 g) in dichloromethane (100 mL)
at 5 oC was added EXAMPLE 158C (26.1 g) in dichloromethane (250 mL) over 1 hour. The
reaction mixture was stirred an for additional 30 minutes at 5oC, and then allowed to warm to
room temperature overnight. The reaction mixture was quenched with pH 7 buffer (100 mL),
and then neutralized with solid potassium carbonate. The resulting mixture was extracted
with ether ), and the combined extracts were washed with brine, dried over sodium
sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica
gel eluting with 1 to 10% ethyl acetate in hexanes to provide the title compound.
EXAMPLE 158E
methyl 3-(1-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptanyl)methyl)methyl-1H-1,2,3-
triazolyl)fluoropicolinate
EXAMPLE 158B (75 mg), EXAMPLE 158D (35 mg) and PdCl2(PPh3)2 (8.8 mg)
were combined in a sealed tube with N,N-dimethylformamide (0.6 mL) and the mixture was
d with nitrogen and then heated to 100oC overnight. Saturated aqueous KF (2 mL) and
ethyl acetate (2 mL) were added and the mixture was stirred for 1 hour, then filtered through
diatomaceous earth, rinsing the filter cake with ethyl acetate (15 mL). The layers were
separated and the aqueous layer was extracted with ethyl e (2 x 15 mL). The extracts
were dried (Na2SO4), filtered and concentrated, then ed by flash chromatography on
silica gel using 0 to 50% ethyl acetate in hexanes to provide the title compound.
EXAMPLE 158F
methyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptanyl)methyl)methyl-1H-1,2,3-triazol
yl)picolinate
E 1B (30 mg), EXAMPLE 158E (25 mg) and cesium carbonate (26.0 μL)
were combined in DMSO (336 μL) and the mixture was heated to 65 oC overnight. The
on mixture was then ioned between ethyl acetate (3 x 10 mL) and water (10 mL).
The extracts were dried (Na2SO4), filtered, and concentrated, then purified by flash
chromatography using 0 to 50% ethyl acetate in s to provide the title compound.
EXAMPLE 158G
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[(1S,2R,5S)-
6,6-dimethylbicyclo[3.1.1]heptyl]methyl}methyl-1H-1,2,3-triazolyl)pyridine
carboxylic acid
EXAMPLE 158F (18 mg) was dissolved in dioxane (1 mL) and 1M aqueous LiOH
(0.2 mL) was added. The reaction was heated to 60 oC for 3 hours, then cooled to room
temperature, diluted with 1N aqueous HCl (5 mL) and extracted with ethyl acetate (3 x 10
mL). The organic extracts were dried (Na2SO4), filtered, and concentrated. The residue was
purified by flash chromatography using 0 to 10% methanol in dichloromethane, to provide the
title compound. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.65 -12.94 (br m, 2H),
8.03 (d 1H), 7.79 (d, 1H), 7.60 -7.67 (m, 2H), 7.41 -7.51 (m, 2H), 7.31 -7.40 (m, 2H), 6.99
(d, 1H), 4.99 (s, 2H), 4.16 -4.31 (m, 2H), 3.92 (t, 2H), 3.02 (t, 2H), 2.22 -2.35 (m, 1H), 2.18
(s, 3H), 1.77 -1.96 (m, 4H), 1.69 -1.76 (m, 1H), 1.49 -1.63 (m, 1H), 1.18 (s, 3H), 1.13 (s,
3H), 0.88 (d, 1H).
EXAMPLE 159
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-[(3,3-
dimethylcyclohexyl)(methyl)amino]methylphenyl}pyridinecarboxylic acid
E 159A
(3-Bromomethyl-phenyl)-(3,3-dimethyl-cyclohexyl)-amine
omethylaniline (1000 mg) and 3,3-dimethylcyclohexanone (780 mg) were
added to dichloromethane (25 mL) and the mixture was stirred at room temperature for 15
minutes. Sodium triacetoxyborohydride (1367 mg) was then added and the solution was
stirred at room temperature for 16 hours. Additional 3,3-dimethylcyclohexanone (780 mg)
and sodium triacetoxyborohydride (1367 mg) were added, and the e was stirred for
another 16 hours. The mixture was then washed with a saturated sodium bicarbonate solution
and brine, dried over anhydrous sodium sulfate, ed, and concentrated under vacuum. The
crude material was purified on silica gel using 2.5% ethyl acetate in s to provide the
title compound.
EXAMPLE 159B
(3-Bromomethyl-phenyl)-(3,3-dimethyl-cyclohexyl)-methyl-amine
EXAMPLE 159A (400 mg), methyl iodide (230 mg), and potassium carbonate (224
mg) were added to N,N-dimethylformamide (5 mL) and the mixture was stirred at room
ature for 16 hours. The e was added to water and extracted with diethyl ether.
The organic extract was washed with brine, dried over anhydrous sodium e, and filtered.
The solvent was removed under vacuum to provide the title nd without further
purification.
EXAMPLE 159C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-[(3,3-
dimethylcyclohexyl)(methyl)amino]methylphenyl}pyridinecarboxylic acid utyl
ester
The title compound was prepared by substituting EXAMPLE 159B for EXAMPLE
112A in EXAMPLE 112B.
EXAMPLE 159D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-[(3,3-
dimethylcyclohexyl)(methyl)amino]methylphenyl}pyridinecarboxylic acid
The title compound was ed by substituting EXAMPLE 159C for EXAMPLE
7D in EXAMPLE 7E. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.90 (bs, 1H), 8.04
(d, 1H), 7.80 (d, 1H), 7.63 (d, 1H), 7.52-7.43 (m, 4H), 7.38 (m, 3H), 7.06-6.95 (m, 2H), 5.00
(bs, 2H), 3.93 (t, 2H), 3.03 (t, 2H), 2.15-1.92 (m, 3H), 1.74-1.50 (m, 2H), 1.48-1.15 (m, 5H),
1.10-0.75 (m, 11H).
EXAMPLE 160
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-methyl{[1-
(morpholinyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid
EXAMPLE 160A
ethyl 1-morpholinocyclohexanecarboxylate
Ethyl 1-aminocyclohexancarboxylate hydrogen chloride (5.800 g), triethylamine
(13.62 mL) and 1-bromo(2-bromoethoxy)ethane (4.21 mL) were stirred together in N,N-
ylformamide (50 mL) at 95°C overnight. The reaction mixture was diluted with ethyl
acetate (150 mL), washed with water (100 mL) and brine (100 mL), dried over magnesium
sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 5% to
25% ethyl acetate/hexanes provided the title compound.
EXAMPLE 160B
(1-morpholinocyclohexyl)methanol
The title compound was prepared by substituting EXAMPLE 160A for ethyl 4,4-
difluorocyclohexanecarboxylate in EXAMPLE 73A.
EXAMPLE 160C
4-(1-((1H-pyrazolyl)methyl)cyclohexyl)morpholine
The title compound was prepared by substituting EXAMPLE 160B for (3-
(dimethylamino)phenyl)methanol and 1H-pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole inEXAMPLE 34A.
E 160D
4-(1-((5-methyl-1H-pyrazolyl)methyl)cyclohexyl)morpholine
The title compound was prepared by substituting EXAMPLE 160C for EXAMPLE
63A in EXAMPLE 63B.
EXAMPLE 160E
4-(1-((4-bromomethyl-1H-pyrazolyl)methyl)cyclohexyl)morpholine
The title compound was prepared by substituting E 160D for EXAMPLE
63B in EXAMPLE 63C.
EXAMPLE 160F
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)
(5-methyl((1-morpholinocyclohexyl)methyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting E 160E for EXAMPLE
77D in EXAMPLE 77E.
EXAMPLE 160G
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-methyl{[1-
(morpholinyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 160F for E
8B in E 8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.85 (s, 2H), 9.50
(d, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.57 – 7.41 (m, 4H), 7.41 – 7.30 (m, 2H),
6.98 (d, 1H), 4.97 (s, 2H), 4.59 (s, 1H), 4.10 – 3.51 (m, 8H), 2.95 (m, 6H), 2.42 – 2.03 (m,
4H), 2.00 – 0.97 (m, 8H).
EXAMPLE 161
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-
[cyclohexyl(methyl)amino]-3'-methyl-3,4'-bipyridinecarboxylic acid
EXAMPLE 161A
ohexyliodo-N,3-dimethylpyridinamine
2-Fluoroiodomethylpyridine (700 mg) in N-methylcyclohexanamine (2.2 ml)
was heated at 180ºC in a Biotage Initiator ave reactor for 18 hours. The reaction
mixture was loaded onto a silica gel cartridge, and was eluted with 0 - 100% dichloromethane
in hexanes to provide the title compound.
EXAMPLE 161B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2'-
(cyclohexyl(methyl)amino)-3'-methyl-3,4'-bipyridinecarboxylate
The title compound was prepared by tuting E 161A for EXAMPLE
112A in EXAMPLE 112B.
EXAMPLE 161C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-
[cyclohexyl(methyl)amino]-3'-methyl-3,4'-bipyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 161B for EXAMPLE
1E in EXAMPLE 1F. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.90 (s, 1H), 8.07
(d, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.64 (d, 2H), 7.44 -7.51 (m, 2H), 7.32 -7.42 (m, 2H),
7.10 (d, 1H), 7.03 (d, 1H), 5.05 (s, 2H), 3.97 (t, 2H), 3.44 (t, 1H), 3.05 (t, 2H), 2.96 (s, 3H),
2.06 (s, 3H), 1.69 (d, 7H), 1.31 (d, 2H), 1.12 (q, 1H)
EXAMPLE 162
N-(1,3-benzothiazolyl)(5-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]methyl-
1H-pyrazolyl}[(methylsulfonyl)carbamoyl]pyridinyl)-1,2,3,4-tetrahydroisoquinoline-
8-carboxamide
A solution of EXAMPLE 157E (0.051 g), methanesulfonamide (0.015 g), 1-ethyl
methylamino)propyl]-carbodiimide hydrochlorideHCl (0.037 g) and 4-
dimethylaminopyridine (0.019 g) were stirred together in dichloromethane (1 mL) at room
temperature ght. The reaction mixture was loaded onto silica gel and eluted using a
gradient of 0.5% to 3.25% methanol/dichloromethane to provide the title compound. 1H
NMR (300 MHz, dimethylsulfoxide-d6) G 84 (s, 1H), 11.81 (s, 1H), 8.03 (d, 1H), 7.79
(d, 1H), 7.62 (d, 1H), 7.56 -7.41 (m, 3H), 7.41 -7.32 (m, 2H), 7.29 (s, 1H), 7.00 (d, 1H), 4.96
(s, 2H), 4.00 (d, 2H), 3.93 (t, 2H), 3.16 (s, 3H), 3.11 (s, 3H), 3.03 (t, 2H), 2.13 (s, 3H), 1.71
(d, 1H), 1.58 -1.00 (m, 7H), 0.96 (s, 3H), 0.84 (s, 3H).
EXAMPLE 163
6-[8-(1,3-benzothiazolylcarbamoyl)methyl-3,4-dihydroisoquinolin-2(1H)-yl]{5-
methyl[(1-methylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 163A
2-(tert-butoxycarbonyl)methyl-1,2,3,4-tetrahydroisoquinolinecarboxylic acid
To a solution of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolinecarboxylic
acid (2.25 g) and tetramethylethylenediamine(1.347 mL) in tetrahydrofuran (40 mL) was
added se t-butyllithium (1.6M, 15.21 mL) at -78 °C. The mixture was stirred at -78 °C
for 40 minutes. To the resulting mixture was added iodomethane (5.07 mL) dropwise and the
mixture was stirred at -78 oC for 3 hours, followed by stirring at room temperature overnight.
The reaction mixture was quenched with saturated ammonium chloride. The reaction e
was extracted with ethyl acetate (150 mL), and the organic layer was washed with brine (40
mL x 3), dried over Na2SO4, filtered, and concentrated. The crude product was purified by
flask tography (silica gel, 10% methanol / dichloromethane).
E 163B
tert-butyl 8-(benzo[d]thiazolylcarbamoyl)methyl-3,4-dihydroisoquinoline-2(1H)-
carboxylate
A mixture of EXAMPLE 163A (400 mg ), riazol
yloxytripyrrolidinophosphonium hexafluorophosphate (714 mg), triethylamine (0.383 mL)
and benzo[d]thiazolamine (247 mg) in dichloromethane (10 mL) was stirred ght at
room temperature. The mixture was diluted with ethyl acetate (100 mL), washed with brine
(30 mL x 3), dried over Na2SO4, filtered, concentrated and purified by flash chromotography
(silica gel, petroleum ethyl e=1/1).
EXAMPLE 163C
N-(benzo[d]thiazolyl)methyl-1,2,3,4-tetrahydroisoquinolinecarboxamide
A on of EXAMPLE 163B (150 mg) in dichloromethane (10 mL) was treated
with TFA (1 mL). The reaction mixture was stirred for 2 hours at 30 °C. The reaction
mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous NaHCO3,
brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash
chromotography (silica gel, dichloromethane/methanol=10/1).
EXAMPLE 163D
methyl 6-(8-(benzo[d]thiazolylcarbamoyl)methyl-3,4-dihydroisoquinolin-2(1H)-yl)
bromopicolinate
A solution of EXAMPLE 163C (1 g), methyl 3-bromofluoropicolinate (0.715 g)
and triethylamine (0.775 mL) in 12 mL DMSO was heated at 70 °C overnight followed by
heating at 105 °C for 4 hours. The reaction mixture was diluted with ethyl acetate, washed
three times with water and brine, dried over Na2SO4, filtered, and concentrated. The product
was purified by flash chromotography (silica gel, 5-25% ethyl acetate/hexanes).
E 163E
methyl 6-(8-(benzo[d]thiazolylcarbamoyl)methyl-3,4-dihydroisoquinolin-2(1H)-yl)
(5-methyl((1-methylcyclohexyl)methyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 163D for EXAMPLE
77D and EXAMPLE 82D for EXAMPLE 30A in EXAMPLE 77E.
E 163F
6-[8-(1,3-benzothiazolylcarbamoyl)methyl-3,4-dihydroisoquinolin-2(1H)-yl]{5-
methyl[(1-methylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 163E for E
75B in E 75C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 13.02 – 12.79 (m,
1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.54 (d, 1H), 7.52 (d, 1H), 7.50 – 7.42 (m, 2H), 7.40 – 7.32
(m, 2H), 7.28 (s, 1H), 6.86 (d, 1H), 6.06 (q, 1H), 4.06 – 3.94 (m, 1H), 3.86 (s, 2H), 3.65 (dt,
1H), 3.14 – 3.01 (m, 2H), 2.12 (s, 3H), 1.58 – 1.33 (m, 10H), 1.33 – 1.18 (m, 3H), 0.85 (s,
3H).
E 164
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-cyano-2'-
[cyclohexyl(methyl)amino]-3,4'-bipyridinecarboxylic acid
EXAMPLE 164A
2-(cyclohexyl(methyl)amino)iodonicotinonitrile
The title compound was prepared by substituting 2-fluoroiodonicotinonitrile for 2-
fluoroiodomethylpyridine in EXAMPLE 161A.
EXAMPLE 164B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3'-cyano-
2'-(cyclohexyl(methyl)amino)-3,4'-bipyridinecarboxylate
The title compound was prepared by substituting EXAMPLE 164A for EXAMPLE
112A in EXAMPLE 112B.
EXAMPLE 164C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-cyano-2'-
[cyclohexyl(methyl)amino]-3,4'-bipyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 164B for E
1E in EXAMPLE 1F. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.90 (s, 1H), 8.07
(d, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.64 (d, 2H), 7.44 -7.51 (m, 2H), 7.33 -7.42 (m, 2H),
7.10 (d, 1H), 7.03 (d, 1H), 5.05 (s, 2H), 3.97 (t, 2H), 3.44 (t, 1H), 3.05 (t, 2H), 2.96 (s, 3H),
2.06 (s, 3H), 1.54 -1.84 (m, 7H), 1.21 -1.42 (m, 2H), 1.06 -1.19 (m, 1H).
E 165
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-
methoxycyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid
EXAMPLE 165A
methyl-1H-pyrazolyl)methyl)cyclohexanol
To a cold (-78 oC) solution of n-butyllithium (25 mL, 2.5M) in tetrahydrofuran (30
mL) was added methyl-1H-pyrazole (5.0 g) in tetrahydrofuran (20 mL) dropwise via
syringe. After 1 hour, cyclohexanone (5.1 g) in tetrahydrofuran (20 mL) was added dropwise
and the reaction mixture was allowed to warm to room temperature. The mixture was
quenched by the addition of saturated ammonium chloride solution and ethyl acetate. The
layers were separated and the aqueous layer was extracted with additional ethyl acetate
(twice). The ed organics were dried over Na2SO4, filtered, and concentrated to
provide the crude title compound.
EXAMPLE 165B
1-((1-methoxycyclohexyl)methyl)methyl-1H-pyrazole
The title compound was prepared by tuting CH3I for 1-bromomethoxyethane
and EXAMPLE 165A for EXAMPLE 151B in E 151C.
EXAMPLE 165C
4-iodo((1-methoxycyclohexyl)methyl)methyl-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 165B for EXAMPLE
65E in EXAMPLE 65F.
EXAMPLE 165D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-
methoxycyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 165C for EXAMPLE
75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 8B in EXAMPLE
8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (s, 1H), 8.04 (d, 1H), 7.79 (d,
1H), 7.61 (d, 1H), 7.40 (m, 5H), 7.27 (s, 1H), 6.94 (d, 1H), 4.95 (s, 2H), 4.03 (m, 2H), 3.89 (t,
2H), 3.15 (m, 3H), 3.01 (t, 2H), 2.12 (s, 3H), 1.36 (m, 10H)
EXAMPLE 166
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-methoxy-
3,3-dimethylcyclohexyl)methyl]methyl-1H-1,2,3-triazolyl}pyridinecarboxylic acid
EXAMPLE 166A
,5-dimethyloxaspiro[2.5]octane
The title compound was prepared by tuting 3,3-dimethylcyclohexanone for
cyclohexanone in EXAMPLE 101A.
EXAMPLE 166B
1-(azidomethyl)-3,3-dimethylcyclohexanol
EXAMPLE 166A (1.93 g), ammonium chloride (3.68 g) and sodium azide (4.47 g)
were combined in a flask with methanol (40 mL) and water (16 mL) and the mixture was
heated to reflux overnight, then cooled to room temperature, diluted with water (200 mL) and
extracted with ethyl acetate (3 x 100 mL). The organic extracts were dried (Na2SO4), filtered,
and concentrated. The crude material was ed by flash chromatography on silica gel
using 0 to 10% ethyl acetate in s to provide the title compound.
EXAMPLE 166C
1-(azidomethyl)methoxy-3,3-dimethylcyclohexane
A on of EXAMPLE 166B (1.33 g) was added dropwise to a suspension of NaH
(60% dispersion in mineral oil, 435 mg) in tetrahydrofuran (15 mL) at 0 oC. The mixture was
stirred for 10 minutes at 0 oC and for 30 minutes at room temperature. CH3I (1.55 g) was
added dropwise. The resulting reaction mixture was stirred overnight at rom temperature, and
then quenched with water (100 mL) and extracted with ethyl e (3 x 50 mL). The
extracts were washed with brine, dried (Na2SO4), and filtered. After concentration, the crude
material was purified by flash chromatography on silica gel using 0 to 7% ethyl acetate in
hexanes to afford the title compound.
E 166D
1-((1-methoxy-3,3-dimethylcyclohexyl)methyl)methyl(tributylstannyl)-1H-1,2,3-
triazole
The title compound was prepared by substituting EXAMPLE 166C for EXAMPLE
158A in EXAMPLE 158B.
EXAMPLE 166E
tert-butyl 3-bromofluoropicolinate
The title compound was prepared by substituting 3-bromofluoropicolinic acid for
3-bromochloropicolinic acid in EXAMPLE 1C.
EXAMPLE 166F
tert-butyl 6-fluoro(1-((1-methoxy-3,3-dimethylcyclohexyl)methyl)methyl-1H-1,2,3-
triazolyl)picolinate
The title compound was prepared by tuting EXAMPLE 166D for EXAMPLE
158B and EXAMPLE 166E for EXAMPLE 158D in EXAMPLE 158E.
EXAMPLE 166G
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((1-
methoxy-3,3-dimethylcyclohexyl)methyl)methyl-1H-1,2,3-triazolyl)picolinate
The title nd was prepared by substituting EXAMPLE 166F for EXAMPLE
158E in EXAMPLE 158F.
EXAMPLE 166H
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-methoxy-
3,3-dimethylcyclohexyl)methyl]methyl-1H-1,2,3-triazolyl}pyridinecarboxylic acid
The title nd was prepared by tuting EXAMPLE 166G for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (300 MHz, DMSO-d 6) G ppm 12.85 (s, 1H), 12.64 -12.81
(br s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.66 (d, 1H), 7.62 (d, 1H), 7.42 -7.51 (m, 2H), 7.32 -
7.41 (m, 2H), 7.01 (d, 1H), 5.00 (s, 2H), 4.25 (s, 2H), 3.93 (t, 2H), 3.22 (s, 3H), 3.03 (t, 2H),
2.18 (s, 3H), 1.66 (d, 1H), 1.28 -1.56 (m, 4H), 1.02 -1.24 (m, 3H), 0.96 (s, 3H), 0.86 (s, 3H).
E 167
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({1-[2-(1,1-
dioxidothiomorpholinyl)ethoxy]cyclohexyl}methyl)methyl-1H-pyrazolyl]pyridine
carboxylic acid
E 167A
1-((4-bromomethyl-1H-pyrazolyl)methyl)cyclohexanol
To a solution of EXAMPLE 165B (10.6 g) in N,N-dimethylacetamide (30 mL) was
added N-bromosuccinimide (9.72 g). The mixture was stirred at room ature overnight.
The mixture was diluted with ethyl acetate (400 mL) and washed with aqueous sodium
bisulfite, water, and brine. Evaporation of the solvent gave the crude product which was used
in the next reaction t further purification.
EXAMPLE 167B
1-((1-(allyloxy)cyclohexyl)methyl)bromomethyl-1H-pyrazole
The title compound was prepared by substituting allyl bromide for 1-bromo
methoxyethane and EXAMPLE 167A for EXAMPLE 151B in E 151C.
EXAMPLE 167C
1-((1-(allyloxy)cyclohexyl)methyl)methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-
1H-pyrazole
To a solution of EXAMPLE 167B (1.25 g) in dioxane (30 mL) was added PdCl2 (40
mg), S-Phos ( 0.328 g), pinacolborane (0.77 g)and triethylamine (1.22 g). The mixture was
stirred at reflux under nitrogen for 3 hours. The reaction mixture was diluted with ethyl
acetate (200 mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. Flash column purification (20% ethyl acetate in ) provided the
title compound.
EXAMPLE 167D
tert-butyl 3-(1-((1-(allyloxy)cyclohexyl)methyl)methyl-1H-pyrazolyl)(8-
[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinate
The title compound was prepared by substituting EXAMPLE 167C for EXAMPLE
30A and EXAMPLE 1D for EXAMPLE 75A in EXAMPLE 75B.
EXAMPLE 167E
utyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((1-
(2,3-dihydroxypropoxy)cyclohexyl)methyl)methyl-1H-pyrazolyl)picolinate
To a stirred solution of EXAMPLE 167D (600 mg) and N-methylmorpholine oxide
(489 mg) in 50% aqueous dioxane (10 mL) was added a solution of osmium tetraoxide (1.2
mL, 0.12 M in t-butanol). After stirring for 1 hour, ethyl acetate was added followed by
saturated sodium bisulfite. The reaction mixture was d for 20 minutes. The organic
layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The
combined organic layers were dried (anhydrous Na2SO4), filtered, and trated under
vacuum to give the crude product.
EXAMPLE 167F
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(5-
methyl((1-(2-oxoethoxy)cyclohexyl)methyl)-1H-pyrazolyl)picolinate
A solution of E 167E (600 mg) in acetone (30 mL) was treated with a
solution of sodium periodate (852 mg) in water (5 mL). After about 4 hours, the solvent was
removed by distillation and the residue was extracted with ethyl acetate (3 x 100 mL). The
combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced
re to give crude product which was purified by flash column chromatography (20%
ethyl acetate in hexane) to give the pure product.
EXAMPLE 167G
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({1-[2-(1,1-
dioxidothiomorpholinyl)ethoxy]cyclohexyl}methyl)methyl-1H-pyrazolyl]pyridine
carboxylic acid
To a on of EXAMPLE 167F (72 mg) and thiomorpholine 1,1-dioxide (13.5 mg)
in romethane (3 mL) was added sodium triacetoxyborohydride (32 mg). The mixture
was stirred overnight. The mixture was dissolved in ethyl acetate (200 mL) and washed with
2N s NaOH and brine, and dried over . Filtration and evaporation of the
solvent gave crude product which was dissolved in dichloromethane (2 mL) and TFA (2 mL).
After stirring overnight, the solvent was evaporated. The residue was purified by reverse
phase chromatography using a Gilson system, eluting with 20 -80% acetonitrile in 0.1% TFA
water on to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) G
ppm 12.86 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.42 (m, 5H), 6.97 (d, 1H), 4.96
(s, 2H), 4.10 (s, 3H), 3.53 (m, 8 H), 3.02 (t, 2H), 2.13 (s, 3H), 1.43 (m, 10H).
EXAMPLE 168
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano
methyl{[1-(morpholinyl)cyclohexyl]methyl}-1H-pyrrolyl)pyridinecarboxylic acid
EXAMPLE 168A
ethyl 4-iodomethyl-1H-pyrrolecarboxylate
The title compound was prepared by substituting with ethyl yl-1H-pyrrole
carboxylate for EXAMPLE 65E in EXAMPLE 65F.
EXAMPLE 168B
4-iodomethyl-1H-pyrrolecarboxylic acid
E 168A (1 g) in tetrahydrofuran (30 mL) and methanol (10 mL) was treated
with 2 N aqueous NaOH (20 mL) overnight. The reaction mixture was cooled to 0oC,
acidified to pH 5, diluted with water (30 mL) and concentrated to remove the organic solvent.
The precipitates were collected by filtration, washed with water and dried under vacuum to
e the title compound.
EXAMPLE 168C
4-iodomethyl-1H-pyrrolecarboxamide
To a solution of EXAMPLE 168B (7.7 g) in ydrofuran (20 mL) at 0oC was
added carbonyldiimidazole (14.9 g). The resulting mixture was stirred at room temperature
for 2 hours. The reaction mixture was cooled to 0 oC and ammonium hydroxide (3 mL) was
added. The mixture was stirred at room temperature for 2 hours and concentrated. The
residue was dissolved in ethyl acetate, washed with brine and concentrated to provide the title
compound.
E 168D
4-iodomethyl-1H-pyrrolecarbonitrile
To a solution of EXAMPLE 168C (300 mg) in N,N-dimethylformamide (6 mL) and
pyridine (0.6 mL) at 0 ºC was added dropwise oxalyl chloride (0.35 mL). The mixture was
stirred at room temperature for 30 minutes, diluted with ethyl acetate and washed with
ted NaHCO3 and water extensively. The organic layer was dried over Na2SO4, ed,
and concentrated. The residue was purified by flash chromatography, and eluted with
dichloromethane to provide the title nd.
E 168E
methyl((1-morpholinocyclohexyl)methyl)-1H-pyrrolecarbonitrile
The title compound was prepared by substituting EXAMPLE 160B for (3-
hylamino)phenyl)methanol and EXAMPLE 168D for 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 168F
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano
methyl{[1-(morpholinyl)cyclohexyl]methyl}-1H-pyrrolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 168E for EXAMPLE
75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 8B in EXAMPLE
8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (s, 1H), 8.03 (d, 1H), 7.79 (d,
1H), 7.62 (d, 1H), 7.41 (m, 5H), 6.95 (d, 1H), 6.83 (s, 1H), 4.96 (s, 2H), 4.01 (m, 2H), 3.89 (t,
2H), 3.01 (t, 2H), 2.69 (m, 3H), 2.10 (s, 3H), 1.95 (m, 3H), 1.56 (m, 3H), 1.27 (m, 4H), 0.96
(m, 3H).
EXAMPLE 169
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
hydroxyethoxy)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid
To a solution of EXAMPLE 167F (56 mg) in tetrahydrofuran (10 mL) was added
NaBH4 (15 mg). The mixture was stirred at room ature overnight. The mixture was
added to ethyl acetate (200 mL) and water (60 mL). The organic layer was washed with brine
and dried over Na2SO4. Filtration and evaporation of the solvent gave crude product which
was dissolved in dichloromethane (2 mL) and TFA (2 mL). After sitting on the bench
overnight, the solvent was evaporated. The residue was purified by reverse phase
chromatography using a Gilson system, eluting with 20 -80% acetonitrile in 0.1% TFA water
solution to provide the desired t. 1H 0 MHz, ylsulfoxide-d 6) G ppm
12.85 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.41 (m, 5H), 7.29 (s, 1H), 6.95 (d,
1H), 4.95 (s, 2H), 4.04 (s, 3H), 3.49 (m, 3H), 3.01 (t, 2H), 2.14 (m, 3H), 1.37 (m, 11H).
EXAMPLE 170
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2,3-
dimethoxypropoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic
acid
EXAMPLE 170A
1-((5-methyl-1H-pyrazolyl)methyl)cycloheptanol
The title compound was prepared by substituting cycloheptanone for cyclohexanone
in E 165A.
EXAMPLE 170B
1-((1-(allyloxy)cycloheptyl)methyl)methyl-1H-pyrazole
The title nd was prepared by substituting allyl bromide for o
methoxyethane and EXAMPLE 170A for EXAMPLE 151B in EXAMPLE 151C.
EXAMPLE 170C
3-(1-((5-methyl-1H-pyrazolyl)methyl)cycloheptyloxy)propane-1,2-diol
To a stirred on of EXAMPLE 170B (248 mg) and N-methylmorpholine oxide
(586 mg) in 50% aqueous dioxane (10 mL) was added a solution of osmium xide (1 mL,
0.12 M). After stirring for 3 hours, ethyl acetate was added followed by saturated sodium
bisulfite. The reaction mixture was stirred for 20 minutes. The organic layer was separated
and the aqueous layer was extracted with ethyl acetate (3x 60 mL). The combined organic
layers were dried (anhydrous Na2SO4), filtered, and concentrated under vacuum to give the
crude product.
EXAMPLE 170D
1-((1-(2,3-dimethoxypropoxy)cycloheptyl)methyl)methyl-1H-pyrazole
The title compound was prepared by substituting methyl iodide for 1-bromo
methoxyethane and EXAMPLE 170C for EXAMPLE 151B in EXAMPLE 151C.
EXAMPLE 170E
1-((1-(2,3-dimethoxypropoxy)cycloheptyl)methyl)iodomethyl-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 170D for EXAMPLE
65E in EXAMPLE 65F.
EXAMPLE 170F
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2,3-
oxypropoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic
acid
The title compound was ed by substituting EXAMPLE 170E for EXAMPLE
75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 8B in E
8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.84 (s, 1H), 8.03 (d, 1H), 7.79 (d,
1H), 7.61 (d, 1H), 7.41 (m, 5H), 7.27 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 4.04 (m, 3H), 3.89 (t,
2H), 3.44 (d, 2H), 3.35 (m, 4H), 3.28 (s, 3H), 3.19 (m, 3H), 3.00 (t, 2H), 2.14 (s, 3H), 1.51
(m, 14H).
EXAMPLE 171
N-(1,3-benzothiazolyl){5-[5-cyano(cyclohexylmethyl)methyl-1H-pyrrolyl]
[(methylsulfonyl)carbamoyl]pyridinyl}-1,2,3,4-tetrahydroisoquinolinecarboxamide
1-Ethyl[3-(dimethylamino)propyl]-carbodiimide hydrochloride (34.6 mg), 4-
dimethylaminopyridine (55.2 mg,), EXAMPLE 130G (95 mg), and methanesulfonamide
(17.19 mg) in dichloromethane (2 mL) was stirred overnight and concentrated. The residue
was purified by reverse phase chromatography, and eluted with 40 -80% acetonitrile in 0.1%
TFA water solution to provide the desired product. 1H NMR (400 MHz, dimethylsulfoxided6
) G ppm 12.86 (s, 1H), 11.81 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.42 -7.54
(m, 3H), 7.33 -7.40 (m, 2H), 7.00 (d, 1H), 6.80 (s, 1H), 4.97 (s, 2H), 3.94 (t, 2H), 3.83 (d,
2H), 3.13 (s, 3H), 3.03 (t, 2H), 2.09 (s, 3H), 1.49 -1.74 (m, 6H), 1.09-1.26 (m, 3H), 0.92 -
1.05 (m, 2H).
EXAMPLE 172
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano{[1-
hoxyethoxy)cycloheptyl]methyl}methyl-1H-pyrrolyl)pyridinecarboxylic acid
EXAMPLE 172A
1-((1-hydroxycycloheptyl)methyl)methyl-1H-pyrrolecarbonitrile
1-Oxaspiro[2.6]nonane (2.5 g), 5-methyl-1H-pyrrolecarbonitrile (2.1 g) and
Cs2CO3 (6.45 g) in N,N-dimethylformamide (15 mL) was heated at 120oCin a Biotage
Initiator microwave reactor for 30 minutes. The reaction mixture was diluted with ethyl
acetate, washed with water and concentrated. The residue was purified by e phase
chromatography, and was eluted with 30% -70% acetonitrile in 0.1% TFA water solution to
e the title compound.
EXAMPLE 172B
1-((1-(2-methoxyethoxy)cycloheptyl)methyl)methyl-1H-pyrrolecarbonitrile
The title compound was prepared by substituting EXAMPLE 172A for EXAMPLE
151B in EXAMPLE 151C.
EXAMPLE 172C
4-bromo((1-(2-methoxyethoxy)cycloheptyl)methyl)methyl-1H-pyrrolecarbonitrile
EXAMPLE 172B (218 mg) in acetonitrile (10 ml) was treated with N-
bromosuccinimide (140 mg) for 15 minutes and concentrated. The residue was purified by
flash chromatography, and was eluted with 0 - 100% hexanes in romethane to provide
the title nd.
EXAMPLE 172D
methyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)
bromopicolinate
The title compound was prepared by substituting methyl 3-bromofluoropicolinate
for EXAMPLE 1C in EXAMPLE 1D.
EXAMPLE 172E
methyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)picolinate
The title compound was prepared by substituting EXAMPLE 172D for EXAMPLE
63C in EXAMPLE 63D.
EXAMPLE 172F
methyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(5-cyano
-methoxyethoxy)cycloheptyl)methyl)methyl-1H-pyrrolyl)picolinate
The title compound was prepared by substituting EXAMPLE 172E for EXAMPLE
30A and E 172C for EXAMPLE 112A in EXAMPLE 112B.
E 172G
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano{[1-
(2-methoxyethoxy)cycloheptyl]methyl}methyl-1H-pyrrolyl)pyridinecarboxylic acid
EXAMPLE 172F (50 mg) in tetrahydrofuran (5 mL) and methanol (3 mL) was
treated with 2 N s NaOH (3 mL) overnight, acidified to pH 1, and concentrated. The
residue was suspended in water and the precipitates were collected, washed with water and
dried over Na2SO4 to give the title compound. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G
ppm 12.86 (s, 2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.41 -7.50 (m, 3H), 7.33 -7.39
(m, 2H), 6.95 (d, 1H), 6.79 (s, 1H), 4.96 (s, 2H), 3.99 (s, 2H), 3.89 (t, 2H), 3.44 -3.51 (m,
2H), 3.21 (s, 2H), 3.01 (t, 2H), 2.12 (s, 3H), 1.37 -1.70 (m, 12H).
EXAMPLE 173
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(1,4-
dioxanylmethoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic
acid
EXAMPLE 173A
1-((1-((1,4-dioxanyl)methoxy)cycloheptyl)methyl)methyl-1H-pyrazole
To a stirred solution of EXAMPLE 170C (315 mg) in dichloromethane (10 mL) was
added NaH (80 mg) at 0oC. The mixture was stirred for 10 minutes. A solution of vinyl
selenone (240 mg) in dichloromethane (5 mL) was added to the mixture and the mixture was
stirred at room temperature for 3 hours. The mixture was quenched with aqueous NH4Cl,
extracted with dichloromethane (2 x 200 mL), washed with water and brine, and dried over
Na2SO4. Filtration and evaporation of the solvent gave the crude product which was purified
by column eluted with 50% ethyl acetate in hexane) to provide the title compound.
EXAMPLE 173B
1-((1-((1,4-dioxanyl)methoxy)cycloheptyl)methyl)iodomethyl-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 173A for EXAMPLE
65E in EXAMPLE 65F.
EXAMPLE 173C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(1,4-
dioxanylmethoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic
acid
The title compound was prepared by substituting E 173B for EXAMPLE
75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 8B in E
8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.84 (s, 1H), 8.03 (d, 1H), 7.79 (d,
1H), 7.61 (d, 1H), 7.42 (m, 5H), 7.27 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 4.02 (m, 4H), 3.89
(m, 2H), 3.59 (m, 5H), 3.42 (m, 3H), 3.02 (m, 2H), 2.13 (s, 3H), 1.33 (m, 14H)
EXAMPLE 174
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl({1-
[2-(morpholinyl)oxoethoxy]cyclohexyl}methyl)-1H-pyrazolyl]pyridinecarboxylic
acid
E 174A
2-(1-((4-bromomethyl-1H-pyrazolyl)methyl)cyclohexyloxy)acetaldehyde
To a solution of EXAMPLE 167B (3.13 g) in dioxane/water (3:1, 40 mL) was added
2,6-lutidine (2.5 mL), OsO4 (2.5% in tert-butanol, 2.75 mL), and NaIO4 (8.55 g) under argon.
The on mixture was stirred at room ature for 4 hours, then water (50 mL) and
romethane (200 mL) were added. The organic layer was separated, and the water phase
was extracted by dichloromethane (3x 200 mL). The combined organic layers were washed
with brine (200 mL) and dried over Na2SO4. After filtration, the solvent was removed to give
the crude product which was used in the next step without further purification.
EXAMPLE 174B
2-(1-((4-bromomethyl-1H-pyrazolyl)methyl)cyclohexyloxy)acetic acid
To a solution of EXAMPLE 174A (3.15 g) in t-butanol (200 mL) and tetrahydrofuran
(50 mL) was added 2-methylbutene (8 mL). The mixture was d to stir in an ice
bath. NaClO2 (1.2 g) and NaH2PO4 (3 g) were dissolved into water (75 mL), and the solution
was added to the mixture. The mixture was allowed to stir in an ice bath for 15 minutes, and
then stirred at room temperature for 12 hours. NH4Cl was added, the mixture was extracted
with ethyl acetate, and the c layer was washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated to dryness to provide the title compound.
E 174C
2-(1-((4-bromomethyl-1H-pyrazolyl)methyl)cyclohexyloxy)morpholinoethanone
To a solution of EXAMPLE 174B (331 mg) in dichloromethane (10 mL) was added
morpholine (174 mg), 4-dimethylaminopyridine (122 mg) and 1-ethyl[3-
(dimethylamino)propyl]-carbodiimide hydrochloride (287 mg). The mixture was stirred
overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with water and
brine and dried over Na2SO4. Filtration and ation of the solvent gave the crude title
compound.
EXAMPLE 174D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl({1-
[2-(morpholinyl)oxoethoxy]cyclohexyl}methyl)-1H-pyrazolyl]pyridinecarboxylic
acid
The title nd was prepared by substituting EXAMPLE 174C for EXAMPLE
75A in EXAMPLE 75B, and then substituting that t for EXAMPLE 8B in EXAMPLE
8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.84 (s, 1H), 8.03 (d, 1H), 7.79 (d,
1H), 7.61 (d, 1H), 7.42 (m, 5H), 7.29 (s, 1H), 6.96 (d, 1H), 4.95 (s, 2H), 4.09 (m, 4H), 3.89 (t,
2H), 3.01 (t, 2H), 2.13 (s, 3H), 1.65 (m, 2H), 1.35 (m, 10H).
EXAMPLE 175
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2,3-
dihydroxypropoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic
acid
E 175A
3-(1-((4-iodomethyl-1H-pyrazolyl)methyl)cycloheptyloxy)propane-1,2-diol
The title compound was prepared by substituting EXAMPLE 170C for EXAMPLE
65E in EXAMPLE 65F.
EXAMPLE 175B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2,3-
dihydroxypropoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic
acid
The title compound was prepared by substituting EXAMPLE 175A for EXAMPLE
75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 8B in EXAMPLE
8C. 134. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (s, 1H), 8.04 (d, 1H), 7.79
(d, 1H), 7.62 (d, 1H), 7.42 (m, 6H), 7.28 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 4.34 (m, 2H),
3.89 (m, 2H), 3.38 (m, 6H), 3.13 (m, 4H), 3.01 (t, 2H), 2.13 (m, 3H), 1.43 (m, 12H).
EXAMPLE 176
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano{[1-
(dimethylamino)cyclohexyl]methyl}methyl-1H-pyrrolyl)pyridinecarboxylic acid
EXAMPLE 176A
(1-(dimethylamino)cyclohexyl)methanol
To a solution of (1-aminocyclohexyl)methanol (378 mg) in ethanol (10 mL) was
added CH3I (2.1 g) and NaHCO3 (246 mg). The mixture was stirred for 24 hours. The
mixture was dissolved in 2N aqueous NaOH (20 mL) and ethyl acetate (200 mL). The
organic layer was dried over Na2SO4, ed, and concentrated under vacuum to give the
crude title compound.
EXAMPLE 176B
(dimethylamino)cyclohexyl)methyl)iodomethyl-1H-pyrrolecarbonitrile
The title compound was prepared by substituting EXAMPLE 176A for (3-
(dimethylamino)phenyl)methanol and EXAMPLE 168D for 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole in EXAMPLE 34A.
EXAMPLE 176C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano{[1-
hylamino)cyclohexyl]methyl}methyl-1H-pyrrolyl)pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 176B for E
75A in EXAMPLE 75B, and then tuting that product for EXAMPLE 8B in E
8C. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm 12.86 (s, 1H), 8.75 (m, 1H), 8.04 (d,
1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.43 (m, 5H), 6.98 (d, 1H), 6.96 (s, 1H), 4.98 (s, 2H), 4.41 (s,
2H), 3.90 (t, 2H), 2.99 (m, 8H), 2.13 (m, 3H), 1.31 (m, 10H).
EXAMPLE 177
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-
[(cyclohexylcarbonyl)(methyl)amino]methylphenyl}pyridinecarboxylic acid
EXAMPLE 177A
cyclohexanecarboxylic acid (3-bromomethyl-phenyl)-methyl-amide
3-Bromo-N,2-dimethylaniline (150 mg) and diisopropylethylamine (291 mg) were
added to dichloromethane (5 mL). Cyclohexanecarbonyl chloride (115 mg) was added and
the solution was stirred at room temperature for 16 hours. The solution was diluted with ethyl
e and washed two times with 1M aqueous HCl and once with brine. The solution was
dried on anhydrous sodium sulfate, filtered, and the solvent was removed to e the title
compound which was used without further purification.
EXAMPLE 177B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-
[(cyclohexylcarbonyl)(methyl)amino]methylphenyl}pyridinecarboxylic acid tert-butyl
ester
The title compound was prepared by tuting EXAMPLE 177A for EXAMPLE
112A in EXAMPLE 112B.
EXAMPLE 177C
1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-
[(cyclohexylcarbonyl)(methyl)amino]methylphenyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 177B for EXAMPLE
7D in EXAMPLE 7E. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 8.03 (d, 1H), 7.79
(d, 1H), 7.63 (d, 1H), 7.55-7.42 (m, 3H), 7.36 (q, 2H), 7.28-7.18 (m, 2H), 7.07-7.01 (m, 2H),
.00 (bs, 2H), 3.94 (t, 2H), 3.04 (bs, 5H), 2.00 (m, 1H), 1.85 (bs, 3H), 1.65-1.35 (m, 6H), (m,
3H), 1.11-0.99 (m, 2H), 0.96-0.80 (m, 2H).
EXAMPLE 178
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,3-
dimethyl[2-(methylsulfonyl)ethoxy]cyclohexyl}methyl)methyl-1H-pyrazol
yl]pyridinecarboxylic acid
EXAMPLE 178A
4-bromo((3,3-dimethyl(2-(methylsulfonyl)ethoxy)cyclohexyl)methyl)methyl-1H-
pyrazole
To a solution of EXAMPLE 157B (0.218 g) in tetrahydrofuran (2.5 mL) was added
sodium hydride (0.027 g) and the on mixture was stirred for 15 s at room
temperature. Methylsulfonylethene (0.095 mL) was added and the reaction was stirred at
room temperature overnight. The reaction was cooled and diluted with ethyl acetate (50 mL).
The organic layer was washed with water (50 mL) and brine (50 mL), dried over ium
e, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 1-
% ethyl acetate in hexanes provided the title compound.
EXAMPLE 178B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3,3-
dimethyl(2-(methylsulfonyl)ethoxy)cyclohexyl)methyl)methyl-1H-pyrazol
yl)picolinate
The title compound was prepared by substituting EXAMPLE 178A for EXAMPLE
77D in EXAMPLE 77E.
EXAMPLE 178C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,3-
dimethyl[2-(methylsulfonyl)ethoxy]cyclohexyl}methyl)methyl-1H-pyrazol
yl]pyridinecarboxylic acid
The title compound was prepared by tuting EXAMPLE 178B for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (400 MHz, dimethylsulfoxide-d 6) δ ppm 6 (s, 2H), 8.04 (d,
1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.56 – 7.41 (m, 3H), 7.40 – 7.33 (m, 2H), 7.32 (s, 1H), 6.96
(d, 1H), 4.96 (s, 2H), 4.16 – 3.96 (m, 2H), 3.95 – 3.79 (m, 3H), 3.79 – 3.68 (m, 1H), 3.32 (d,
3H), 3.01 (t, 2H), 2.94 (s, 3H), 2.14 (s, 3H), 1.74 (d, 1H), 1.52 (t, 2H), 1.45 – 1.27 (m, 2H),
1.27 – 1.02 (m, 5H), 1.00 (s, 3H), 0.86 (s, 3H).
EXAMPLE 179
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-methyl
{methyl[(1-methylcyclohexyl)carbonyl]amino}phenyl)pyridinecarboxylic acid
EXAMPLE 179A
1-Methyl-cyclohexanecarboxylic acid (3-bromomethyl-phenyl)-methyl-amide
The title compound was prepared by tuting 1-methylcyclohexanecarbonyl
chloride for cyclohexanecarbonyl chloride in EXAMPLE 177A.
EXAMPLE 179B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-methyl
{methyl[(1-methylcyclohexyl)carbonyl]amino}phenyl)pyridinecarboxylic acid tert-butyl
ester
The title compound was ed by substituting EXAMPLE 179A for EXAMPLE
112A in EXAMPLE 112B.
EXAMPLE 179C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-methyl
{methyl[(1-methylcyclohexyl)carbonyl]amino}phenyl)pyridinecarboxylic acid
The title compound was ed by substituting EXAMPLE 179B for EXAMPLE
7D in EXAMPLE 7E. 1H NMR (400 MHz, ylsulfoxide-d 6) G ppm (8.03,1H), 7.79 (d,
1H), 7.63 (d, 1H), 7.50-7.32 (m, 5H), 7.18 (m, 2H), 7.02 (m, 2H), 4.99 (bs, 2H), 3.93 (t, 2H),
3.02 (bs, 5H), 1.91 (s, 3H), 1.85-1.62 (m, 2H), 1.44-1.10 (m, 8H), 0.95 (m, 3H).
EXAMPLE 180
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethoxy)-3,3-dimethylcyclohexyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid
EXAMPLE 180A
1-((1-(allyloxy)-3,3-dimethylcyclohexyl)methyl)bromomethyl-1H-pyrazole
To a solution of E 157B (2.73 g) in methylformamide (20 mL) was
added NaH (1.45 g) and the reaction mixture was stirred for 30 minutes at room temperature.
3-Bromopropene (1.53 mL) was added and the mixture was stirred at room temperature for
2 hours. The reaction mixture was diluted with diethyl ether (75 mL), washed with water (2 x
50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica
gel chromatography eluting with a gradient of 1.5% to 15% ethyl acetate/hexanes provided
the title compound.
EXAMPLE 180B
2-(1-((4-bromomethyl-1H-pyrazolyl)methyl)-3,3-dimethylcyclohexyloxy)ethanol
A solution of EXAMPLE 180A (2.80 g) in dioxane/water (30 mL/10 mL) was added
to 2,6-dimethylpyridine (1.909 mL) and sodium periodate (7.02 g) followed by the addition of
osmium tetroxide (2.5% solution, 1.0 mL) and the reaction mixture was stirred for 30 minutes
at room temperature. The on mixture was diluted with ethyl acetate (50 mL), washed
with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and
concentrated. The residue was dissolved in ol (20 mL) and sodium borohydride (0.16
g) was added. The mixture was d at room temperature for 1 hour. An aqueous work up
followed by silica gel chromatography using 2-30% ethyl acetate in hexanes provided the title
compound.
EXAMPLE 180C
4-bromo((1-(2-methoxyethoxy)-3,3-dimethylcyclohexyl)methyl)methyl-1H-
To a solution of EXAMPLE 180B (2.2 g) in N,N-dimethylformamide (20 mL) was
added sodium hydride (0.38 g). After stirring for 30 minutes, methyl iodide (0.60 mL) was
added. The reaction mixture was d for 2 hours at room temperature, diluted with ether
(100 mL) and washed with water (2 x 75 mL) and brine (75 mL), dried over magnesium
sulfate, filtered, and concentrated. Silica gel tography g with a gradient of 3% to
% ethyl acetate/hexanes provided the title compound.
EXAMPLE 180D
1-((1-(2-methoxyethoxy)-3,3-dimethylcyclohexyl)methyl)methyl(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 180C for E
63C in EXAMPLE 63D.
EXAMPLE 180E
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2-
methoxyethoxy)-3,3-dimethylcyclohexyl]methyl}methyl-1H-pyrazolyl)pyridine
carboxylic acid
The title compound was ed by substituting EXAMPLE 180D for EXAMPLE
157D in EXAMPLE 157E. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.84 (s, 1H),
8.03 (d 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.53 – 7.40 (m, 3H), 7.36 (m, 2H), 7.28 (s, 1H), 6.95
(d, 1H), 4.95 (s, 2H), 4.10 – 3.93 (m, 2H), 3.89 (t, 2H), 3.62 – 3.45 (m, 4H), 3.23 (s, 3H), 3.01
(t, 2H), 2.12 (s, 3H), 1.79 (d, 1H), 1.63 – 1.01 (m, 7H), 0.99 (s, 3H), 0.84 (s, 3H).
EXAMPLE 181
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-cyano
[(cyclohexylsulfonyl)(methyl)amino]phenyl}pyridinecarboxylic acid
EXAMPLE 181A
cyclohexanesulfonic acid methylamide
Cyclohexanesulfonyl chloride (500 mg) was added to methylamine (12.3 mL, 2M
solution in tetrahydrofuran) and the reaction e was stirred at room temperature for one
hour. The solution was added to 1M aqueous HCl and extracted with ethyl acetate. The
extract was washed with brine and dried over anhydrous sodium sulfate. After filtration, the
solvent was removed under vacuum to yield the product.
EXAMPLE 181B
cyclohexanesulfonic acid (3-bromocyano-phenyl)-methyl-amide
2-Bromofluorobenzonitrile (500 mg), EXAMPLE 181A (487 mg), and potassium
carbonate (415 mg) were added to N,N-dimethylacetamide (15 mL) and the mixture was
heated to 85oC for three days. The mixture was cooled, added to 1M aqueous HCl, extracted
with 70% ethyl acetate (hexanes), washed with water, washed with brine, and dried over
ous sodium sulfate. After filtration, the solvent was removed under vacuum, and the
crude material was recrystallized from ethyl acetate to provide the title nd.
EXAMPLE 181C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-cyano
[(cyclohexylsulfonyl)(methyl)amino]phenyl}pyridinecarboxylic acid tert-butyl ester
The title compound was ed by substituting EXAMPLE 181B for EXAMPLE
112A in EXAMPLE 112B.
EXAMPLE 181D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-cyano
[(cyclohexylsulfonyl)(methyl)amino]phenyl}pyridinecarboxylic acid
The title nd was prepared by tuting EXAMPLE 181C for EXAMPLE
7D in EXAMPLE 7E. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G 85 (bs, 1H),
8.03 (d, 1H), 7.79 (d, 1H), 7.71 (dd, 1H), 7.63 (d, 1H), 7.60 (dd, 1H), 7.49-7.32 (m, 6H), 7.10
(d, 1H), 5.05 (bs, 2H), 3.98 (t, 2H), 3.28 (s, 3H), 3.04 (t, 2H), 2.14 (d, 2H), 1.79 (d, 2H), 1.62
(d, 1H), 1.51-1.10 (m, 6H).
E 182
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-cyano[2-
(tricyclo[3.3.1.13,7]decyl)pyrrolidinyl]phenyl}pyridinecarboxylic acid
EXAMPLE 182A
2-(2-adamantanyl-pyrrolidinyl)bromo-benzonitrile
2-Bromofluorobenzonitrile (900 mg), 2-adamantanyl-pyrrolidine (924 mg), and
potassium carbonate (1244 mg) were added to dimethyl sulfoxide and the mixture was heated
at 130oC for 16 hours. The solution was cooled, diluted with ethyl acetate, washed twice with
1M HCl, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the
crude al was concentrated under vacuum and purified on silica gel using 5% ethyl
acetate (hexanes) to provide the title compound.
EXAMPLE 182B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-cyano{2-
[tricyclo[3.3.1.13,7]decyl]pyrrolidinyl}phenyl)pyridinecarboxylic acid tert-butyl ester
The title compound was prepared by substituting EXAMPLE 182A for EXAMPLE
112A in EXAMPLE 112B.
EXAMPLE 182C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-cyano[2-
(tricyclo[3.3.1.13,7]decyl)pyrrolidinyl]phenyl}pyridinecarboxylic acid
The title compound was prepared by substituting EXAMPLE 182B for E
7D in EXAMPLE 7E. 1H NMR (400 MHz, dimethylsulfoxide-d 6) G ppm 12.85 (bs, 1H),
12.68 (bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.65 (d, 1H), 7.62 (d, 1H), 7.50-7.44 (m, 2H), 7.40-
7.27 (m, 4H), 7.03 (d, 1H), 6.65 (d,1H), 5.02 (bs, 2H), 3.96 (m, 2H), 3.63 (m, 1H), 3.18 (m,
2H), 3.04 (t, 2H), 1.91-1.82 (m, 5H), 1.68-1.42 (m, 12H), 1.24 (bs, 2H).
EXAMPLE 183
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-2'-
(piperidinyl)-3,4'-bipyridinecarboxylic acid
EXAMPLE 183A
utyl benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2'-chloro-
3'-methyl-3,4'-bipyridinecarboxylate
To a solution of EXAMPLE 30A (1.22 g) in dioxane (4 mL), and aqueous NaHCO3
(2 mL) was added 2-chloroiodomethylpyridine (505 mg), and
tetrakis(triphenylphosphine)palladium(0) (115 mg). The e was stirred at 120oC for 20
minutes in a Biotage tor microwave reactor. The mixture was diluted with ethyl acetate
(300 mL) and washed with water (3 times)and brine, and dried over Na2SO4. tion and
evaporation of the solvent gave crude product which was loaded on a silica gel column and
eluted with 20 % ethyl acetate in dichloromethane to provide the title compound.
EXAMPLE 183B
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-2'-
(piperidinyl)-3,4'-bipyridinecarboxylic acid
To a solution of EXAMPLE 183A (200 mg) in N,N-dimethylacetamide (15 mL) was
added piperidine (110 mg), K3PO4 (218 mg), and bis(tri-tert-butylphosphine)palladium (7.01
mg). The mixture was stirred at 100 oC overnight under nitrogen. The mixture was diluted
with ethyl acetate (300 mL), washed with water and brine, and dried over . tion
and evaporation of the solvent gave crude product which was purified by flash
chromatography to give the pure ester which was dissolved in dichloromethane/TFA (1:1, 6
mL) and stirred overnight. The solvent was evaporated under vacuum and the residue was
dissolved in ethanol (1:1, 10 ml). The residue was purified by reverse phase
chromatography using a Gilson system, g with 20 -80% acetonitrile in 0.1% TFA water
solution to provide the desired product. 1H NMR (300 MHz, dimethylsulfoxide-d 6) G ppm
12.86 (s, 1H), 8.05 (m, 2H), 7.79 (d, 1H), 7.48 (m, 5H), 7.05 (d, 1H), 6.87 (d, 1H), 5.02 (s,
2H), 3.95 (t, 2H), 3.07 (m, 5H), 2.01 (s, 3H), 1.65 (m, 6H).
EXAMPLE 184
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(1-cyclohexyl-
oxypropyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid
EXAMPLE 184A
3-cyclohexyl(1H-pyrazolyl)propanol
To a solution of EXAMPLE 152A (2.42 g) in toluene (20 mL) diisobutylaluminum
hydride (28.2 mL) was added at -78 °C. The reaction mixture was stirred for 60 minutes.
The reaction mixture was quenched with methanol (10 mL), 1M aqueous HCl (200 mL) and
washed with ted NaHCO3. The organic layer was dried over magnesium sulfate,
filtered and concentrated. The product was purified by flash chromotography (silica gel, 10-
100% ethyl acetate/hexanes) to provide the title compound.
EXAMPLE 184B
1-(1-cyclohexylmethoxypropyl)-1H-pyrazole
To a on of EXAMPLE 184A (0.23 g) in dry tetrahydrofuran (5 mL) was added
sodium e (0.166 g) at 0 °C. The reaction mixture was stirred for 60 minutes when
methyl iodide (0.259 mL) was added and stirring was continued for 4 hours at room
temperature. The reaction mixture was quenched with ammonium chloride solution (5 mL),
and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered
and trated. The crude material was purified by flash chromatography on silica gel, and
was eluted with 10-60% ethyl acetate/hexanes.
EXAMPLE 184C
1-(1-cyclohexylmethoxypropyl)methyl-1H-pyrazole
The title compound was ed by substituting EXAMPLE 184B for EXAMPLE
63A in EXAMPLE 63B.
EXAMPLE 184D
4-bromo(1-cyclohexylmethoxypropyl)methyl-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 184C for EXAMPLE
63B in EXAMPLE 63C.
EXAMPLE 184E
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(1-
cyclohexylmethoxypropyl)methyl-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 184D for EXAMPLE
77D in EXAMPLE 77E.
EXAMPLE 184F
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(1-cyclohexyl-
3-methoxypropyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid
The title nd was prepared by substituting EXAMPLE 184E for EXAMPLE
1E in E 1F. 1H NMR (300 MHz, dimethylsulfoxide-d 6) δ ppm 12.85 (s, 1H), 8.04
(d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.52 – 7.40 (m, 3H), 7.41 – 7.29 (m, 3H), 6.95 (d, 1H),
4.95 (s, 2H), 3.97 – 3.84 (m, 4H), 3.15 – 3.07 (m, 1H), 3.10 (s, 3H), 3.01 (t, 2H), 2.64 (td,
1H), 2.16 – 2.05 (m, 1H), 2.04 (s, 3H), 2.00 – 1.82 (m, 2H), 1.81 – 1.65 (m, 2H), 1.65 – 1.50
(m, 2H), 1.29 – 0.75 (m, 6H).
E 185
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,3-
dimethyl[2-(methylamino)ethoxy]cyclohexyl}methyl)methyl-1H-pyrazolyl]pyridine-
2-carboxylic acid
EXAMPLE 185A
methyl((5-methyl-1H-pyrazolyl)methyl)cyclohexanol
To a cold (-78°C) on of nBuLi (12.48 mL) in tetrahydrofuran (40 mL) was
added a solution of 1,5-dimethyl-1H-pyrazole (3.0 g) in tetrahydrofuran (3 mL) dropwise.
After stirring for 1 hour, a solution of methylcyclohexanone (3.94 g) in tetrahydrofuran
(3 mL) was added dropwise, and the reaction was allowed to warm to 0°C. After stirring for
1 hour, the reaction mixture was diluted with ether (100 mL), washed with water (50 mL) and
brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Purification of the
residue by silica gel chromatography, eluting with a gradient of 3% to 25% ethyl acetate in
hexanes, gave the title compound.
EXAMPLE 185B
1-((4-bromomethyl-1H-pyrazolyl)methyl)-3,3-dimethylcyclohexanol
The title compound was prepared by substituting EXAMPLE 185A for EXAMPLE
63B in EXAMPLE 63C.
EXAMPLE 185C
1-((1-(allyloxy)-3,3-dimethylcyclohexyl)methyl)bromomethyl-1H-pyrazole
To a cold (0 °C) solution of EXAMPLE 185B (3.63 g) in N,N-dimethylformamide
(25 mL) was added NaH (0.964 g, 60% dispersion in mineral oil), and the reaction was stirred
for 30 minutes. opropene (1.529 mL) was added. The cooling bath was removed,
and the reaction was warmed to room temperature. The reaction mixture was heated to 50 °C,
whereupon a significant evolution of gas occurred. After 2 hours, the reaction mixture was
diluted with diethyl ether (75 mL), washed with water (2 x 50 mL) and brine (50 mL), dried
over magnesium sulfate, filtered, and concentrated. cation of the e by silica gel
chromatography, eluting with a gradient of 1.5% to 15% ethyl acetate in hexanes, gave the
title compound.
EXAMPLE 185D
2-(trimethylsilyl)ethyl (2-((1-((4-bromomethyl-1H-pyrazolyl)methyl)-3,3-
ylcyclohexyl)oxy)ethyl)(methyl)carbamate
To a solution of EXAMPLE 185C (0.93 g) in dioxane (9 mL) and water (3 mL) was
added 2,6-dimethylpyridine (0.634 mL) and sodium periodate (2.331 g) followed by osmium
tetroxide (0.277 mL, 2.5% solution in tert-butanol). The reaction e was stirred for 30
minutes at room temperature, whereupon a significant precipitate formed. The reaction
mixture was stirred for an additional 1 hour, d with ether (100 mL), washed with water
(50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and trated. To the
residue dissolved in methanol (5 mL) was added amine (1.635 mL) and sodium
cyanoborohydride (0.171 g). After 1 hour, the reaction mixturewas diluted with ethyl acetate
(50 mL), washed with water (50 mL), brine (50 mL), dried over magnesium sulfate and
concentrated. The residue was dissolved in methylene chloride (5 mL), and 2,5-
dioxopyrrolidinyl methylsilyl)ethyl carbonate (0.848 g) was added. After 1 hour, the
reaction was quenched by the addition of water. The layers were separated, and the organic
layer was dried with ium sulfate, filtered and concentrated. The residue was purified
by silica gel chromatography, g with hexane/ethyl acetate, to give the title product.
EXAMPLE 185E
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,3-
dimethyl[2-(methylamino)ethoxy]cyclohexyl}methyl)methyl-1H-pyrazolyl]pyridine-
2-carboxylic acid
A mixture of E 30A (0.629 g), EXAMPLE 185D (0.430g), 1,3,5,7-
tetramethylphenyl-2,4,8-trioxaphosphaadamantane (0.125 g), potassium phosphate
(0.908 g) and tris(dibenzylidieneacetone)dipalladium(0) form adduct (0.089 g) was
dissolved in tetrahydrofuran (3 mL) and water (1 mL). The reaction vessel was flushed with
nitrogen and then heated under microwave conditions (Biotage) to 140 °C for 5 minutes. The
on e was diluted with ether (25 mL), washed with saturated NH4Cl solution (20
mL) and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated.
Purification of the residue by silica gel chromatography, eluting with a gradient of 5% to
100% ethyl acetate in hexanes, gave an intermediate ester. The residue was dissolved in
methylene chloride (1 mL), and TFA (1 mL) was added. After stirring overnight, the reaction
mixture was concentrated and purified by RP-HPLC, eluting with 10 – 80% acetonitrile in
water containing 0.1% v/v TFA, to give the title compound. 1H NMR (300 MHz,
dimethylsulfoxide-d6) δ 12.85 (s, 1H), 8.70 (s, 2H), 8.03 (d, J = 7.8, 1H), 7.79 (d, 1H), 7.62
(d, 1H), 7.54 -7.41 (m, 4H), 7.36 (m, 2H), 6.97 (d, 1H), 4.97 (s, 2H), 4.06 (s, 2H), 3.90 (t,
2H), 3.74 (m, 2H), 3.12 (s, 2H), 3.02 (t, 2H), 2.65 (t, 3H), 2.14 (s, 3H), 1.35 (m, 97 (s,
3H), 0.86 (s, 3H).
EXAMPLE 186
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-methyl
[(2,6,6-trimethyltetrahydro-2H-pyranyl)methyl]-1H-pyrazolyl}pyridinecarboxylic
acid
E 186A
2,6-dimethyl(5-methyl-1H-pyrazolyl)heptenol
The title compound was prepared by substituting 6-methylheptenone for 3,3-
dimethylcyclohexanone in EXAMPLE 185A.
EXAMPLE 186B
-methyl((2,6,6-trimethyltetrahydro-2H-pyranyl)methyl)-1H-pyrazole
A mixture of EXAMPLE 186A (6.5 g) and formic acid (20 mL) was heated at 100°C
for 3 hours. The reaction mixture was concentrated, and the residue was purified by silica gel
chromatography, eluting with 1% ethyl acetate in petroleum ether, to give the title product.
E 186C
4-bromomethyl((2,6,6-trimethyltetrahydro-2H-pyranyl)methyl)-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 186B for E
63B in EXAMPLE 63C.
EXAMPLE 186D
5-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)((2,6,6-
trimethyltetrahydro-2H-pyranyl)methyl)-1H-pyrazole
The title compound was prepared by substituting EXAMPLE 186C for EXAMPLE
84C in EXAMPLE 84D.
EXAMPLE 186E
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)
(5-methyl((2,6,6-trimethyltetrahydro-2H-pyranyl)methyl)-1H-pyrazolyl)picolinate
The title compound was prepared by substituting EXAMPLE 186D for EXAMPLE
82D in EXAMPLE 82E.
EXAMPLE 186F
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-methyl
[(2,6,6-trimethyltetrahydro-2H-pyranyl)methyl]-1H-pyrazolyl}pyridinecarboxylic
acid
The title compound was prepared by substituting EXAMPLE 186E for E
1E in EXAMPLE 1F. 1H NMR (400 MHz,dimethylsulfoxide-d 6) G ppm 12.84 (v br s, 1H),
8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.45 (m, 3H), 7.36 (m, 2H), 7.27 (s, 1H), 6.96 (d,
1H), 4.95 (s, 2H), 4.00 (d, 2H), 3.88 (br t, 2H), 3.01 (br t, 2H), 2.16 (s, 3H), 1.69 (m, 1H),
1.52 (m, 2H), 1.39 (m, 2H), 1.15 (s, 3H), 1.14 (s, 3H), 1.07 (m, 1H), 1.06 (s, 3H).
EXAMPLE 187
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H-
indazolyl)pyridinecarboxylic acid
EXAMPLE 187A
1-benzyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-indazole
The title compound was ed by substituting 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-indazole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazole and benzyl bromide for EXAMPLE 4A in EXAMPLE 4B.
E 187B
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)
(1-benzyl-1H-indazolyl)picolinate
The title compound was prepared by tuting EXAMPLE 187A for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 187C
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H-
indazolyl)pyridinecarboxylic acid
The title compound was ed by substituting EXAMPLE 187B for EXAMPLE
1E in EXAMPLE 1F. 1H NMR (400 MHz, ylsulfoxide-d 6) G ppm 12.89 (v br s, 1H),
8.03 (d, 1H), 7.87 (s, 1H), 7.78 (m, 2H), 7.64 (m, 2H), 7.46 (m, 2H), 7.40-7.20 (m, 8H), 7.04
(d, 1H), 6.99 (d, 1H), 5.66 (s, 2H), 5.02 (s, 2H), 3.95 (br t, 2H), 3.04 (br t, 2H).
EXAMPLE 188
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H-
o[2,3-c]pyridinyl)pyridinecarboxylic acid
EXAMPLE 188A
1-benzylbromo-1H-pyrrolo[2,3-c]pyridine
The title nd was prepared by substituting 3-bromo-1H-pyrrolo[2,3-c]pyridine
for 3-bromo-1H-pyrrolo[2,3-b]pyridine in EXAMPLE 141A.
EXAMPLE 188B
1-benzyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrrolo[2,3-c]pyridine
The title compound was prepared by substituting EXAMPLE 188A for EXAMPLE
84C in EXAMPLE 84D.
EXAMPLE 188C
tert-butyl 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-
benzyl-1H-pyrrolo[2,3-c]pyridinyl)picolinate
The title compound was prepared by substituting EXAMPLE 188B for EXAMPLE
22A in EXAMPLE 22B.
EXAMPLE 188D
6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H-
pyrrolo[2,3-c]pyridinyl)pyridinecarboxylic acid
The title compound was prepared by substituting E 188C for EXAMPLE
8B in EXAMPLE 8C. 1H NMR (400 MHz, ylsulfoxide-d 6) G ppm 9.42 (s, 1H), 8.47
(s, 1H), 8.32 (d, 1H), 8.04 (d, 1H), 7.89 (d, 1H), 7.79 (d, 1H), 7.76 (d, 1H), 7.64 (br d, 1H),
7.48 (m, 2H), 7.40-7.28 (m, 7H), 7.01 (d, 1H), 5.76 (s, 2H), 5.04 (s, 2H), 3.95 (br t, 2H), 3.05
(br t, 2H).
Claims (23)
1. A compound having Formula (I) (R1)m (R2)n N N Z1 HN O Y1 L1 Y2 (R3)p Formula (I), or a therapeutically acceptable salt thereof, n X is heteroaryl; wherein the heteroaryl represented by X is optionally substituted with one, two, three, or four R4; Y1 is phenylene, or C5-6 heteroarylene; optionally fused to one or two rings ed from the group consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8 heterocycloalkane, and C3-8 heterocycloalkene; wherein Y1 is optionally substituted with one, two, three, or four substituents independently selected from the group consisting of R5, OR5, SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, )N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, SO2R5, C(O)NR5SO2R5, SO2NH2, SO2NHR5, SO2N(R5)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; L1 is selected from the group consisting of (CR6R7)q, (CR6R7)s-O-(CR6R7)r, (CR6R7)s-C(O)-(CR6R7)r, (CR6R7)s-S-(CR6R7)r, (CR6R7)s-S(O)2-(CR6R7)r, (CR6R7)s-NR6AC(O)-(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, (CR6R7)s-NR6A-(CR6R7)r, (CR6R7)s-S(O)2NR6A-(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r; and Y2 is selected from the group consisting of C3-11 branched chain alkyl, C3-7 lkyl, C4-7 cycloalkenyl, , and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 lkenyl, phenyl, and C3-7 heterocyclyl are optionally fused to one or two rings selected from the group consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 arene, C3-8 heterocycloalkane, and C3-8 heterocycloalkene; wherein Y2 is optionally substituted with one, (11395927_1):GGG two, three, four, or five substituents independently selected from the group ting of R8, OR8, SR8, S(O)R8, SO2R8, , CO(O)R8, OC(O)R8, OC(O)OR8, NH2, NHR8, N(R8)2, NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8, NHC(O)OR8, )OR8, NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, SO2R8, C(O)NR8SO2R8, SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; or L1 is a bond; and Y2 is selected from the group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl represented by Y2 are optionally fused to one or two rings selected from the group consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8 heterocycloalkane, and C3-8 heterocycloalkene; wherein each Y2 and each ring fused to Y2 are optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, OC(O)R8, OC(O)OR8, NH2, NHR8, N(R8)2, NHC(O)R8, )R8, 2R8, NR8S(O)2R8, NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, OH, C(O)NHOR8, C(O)NHSO2R8, C(O)NR8SO2R8, SO2NH2, SO2NHR8, 8)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; Z1 is selected from the group consisting of C(O)OR9, C(O)NR10R11, C(O)R11, NR10C(O)R11, NR10C(O)NR10R11, OC(O)NR10R11, O)OR9, C(=NOR10)NR10R11, NR10C(=NCN)NR10R11, NR10S(O)2NR10R11, S(O)2R9, S(O)2NR10R11, N(R10)S(O)2R11, NR10C(=NR11)NR10R11, R10R11, C(=NR10)NR10R11, halogen, NO2, and CN; or Z1 is selected from the group consisting of (11395927_1):GGG N O O N O HN N O N O HN OH N N N H N N N , , , , ,H H O O O O O O OH N N O OH Rk N O N Rk S OH , , , , ,H Rk H O O O O O OH OH O O N N N OH N Rk H , , , ,H H H O Rk O O O O O S N S N S Rk N N N H Rk H H O , , and ; R1, at each occurrence, is independently selected from the group consisting of halo, C1- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; R2, at each occurrence, is independently selected from the group ting of deuterium, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; two R2 that are attached to the same carbon atom, er with said carbon atom, optionally form a ring selected from the group consisting of heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl; R3, at each occurrence, is independently selected from the group consisting of halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; R4, at each occurrence, is independently selected from the group consisting of NR12R13, OR12, CN, NO2, halogen, C(O)OR12, C(O)NR12R13, NR12C(O)R13, NR12S(O)2R14, NR12S(O)R14, S(O)2R14, S(O)R14 and R14; R5, at each occurrence, is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; R6A is independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; R6 and R7, at each occurrence, are each ndently selected from the group consisting of hydrogen, R15, OR15, SR15, S(O)R15, SO2R15, C(O)R15, 15, 15, (11395927_1):GGG OC(O)OR15, NH2, NHR15, N(R15)2, R15, NR15C(O)R15, NHS(O)2R15, NR15S(O)2R15, NHC(O)OR15, NR15C(O)OR15, NHC(O)NH2, NHC(O)NHR15, NHC(O)N(R15)2, O)NHR15, NR15C(O)N(R15)2, C(O)NH2, R15, C(O)N(R15)2, C(O)NHOH, C(O)NHOR15, C(O)NHSO2R15, C(O)NR15SO2R15, SO2NH2, SO2NHR15, SO2N(R15)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; or R8, at each occurrence, is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; n the R8 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl are optionally substituted with one, two, three, four, five, or six substituents independently selected from the group consisting of R16, OR16, SR16, S(O)R16, SO2R16, C(O)R16, CO(O)R16, OC(O)R16, OC(O)OR16, NH2, NHR16, N(R16)2, NHC(O)R16, NR16C(O)R16, NHS(O)2R16, NR16S(O)2R16, NHC(O)OR16, NR16C(O)OR16, NH2, NHC(O)NHR16, NHC(O)N(R16)2, NR16C(O)NHR16, NR16C(O)N(R16)2, C(O)NH2, C(O)NHR16, C(O)N(R16)2, OH, C(O)NHOR16, C(O)NHSO2R16, C(O)NR16SO2R16, SO2NH2, SO2NHR16, SO2N(R16)2, , C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; wherein the R8 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, NH2, C(O)NH2, SO2NH2, C(O)H, (O), OH, CN, NO2, OCF3, OCF2CF3, F, Cl, Br and I; R9 is ed from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, cycloalkyl, phenyl and (CH2)1-4 phenyl; and R10 and R11, at each occurrence, are each independently selected from the group consisting of en, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 haloalkyl, phenyl and phenyl; or R10 and R11, or R10 and R9, together with the atom to which each is attached are combined to form a heterocyclyl; Rk, at each occurrence, is independently ed from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 heterocycloalkyl, C3-7 cycloalkyl and C1-6 haloalkyl; (11395927_1):GGG wherein the Rk C1-6 alkyl, C2-6 l, and C2-6 alkynyl are optionally substituted with aryl, heterocyclyl, cycloalkyl, or lkenyl; R12 and R13, at each occurrence, are each independently ed from the group consisting of hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl and (CH2)1-4 phenyl; R14, at each occurrence, is independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl and C1-4 haloalkyl; R12 and R13, or R12 and R14, at each occurrence, together with the atom to which each is attached, are optionally combined to form a heterocyclyl; R15, at each occurrence, is independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R15 C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, and C1-4 hydroxyalkyl are optionally substituted with one, two, or three substituents ndently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl, NH2, C(O)NH2, , C(O)H, C(O)OH, (O), OH, CN, NO2, OCF3, OCF2CF3, F, Cl, Br and I; R16, at each occurrence, is independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, aryl, cycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl; n the R16 C1-4 alkyl, C2-4 l, C2-4 alkynyl, C1-4 haloalkyl, and C1-4 yalkyl are optionally substituted with one substituent independently selected from the group consisting of OCH3, OCH2CH2OCH3, and OCH2CH2NHCH3; q is 1, 2, or 3; s is 0, 1, 2, or 3; r is 0, 1, 2, or 3; wherein the sum of s and r is 0, 1, or 2; m is 0, 1, 2, or 3; (11395927_1):GGG n is 0, 1, 2, 3, 4, 5, or 6; and p is 0, 1, or 2.
2. The compound or therapeutically acceptable salt of claim 1, wherein Y1 is yl, pyrazolyl, or triazolyl.
3. The compound or therapeutically acceptable salt of claim 1, wherein Y1 is pyridinyl or phenyl.
4. The compound or therapeutically acceptable salt of claim 1, wherein X is d]thiazolyl; which is optionally substituted with one, two, three or four R4.
5. The compound or therapeutically able salt of claim 2, wherein X is benzo[d]thiazolyl; which is ally substituted with one, two, three or four R4.
6. The compound or therapeutically acceptable salt of claim 3, wherein X is benzo[d]thiazolyl; which is optionally substituted with one, two, three or four R4.
7. The compound or therapeutically acceptable salt of claim 2, wherein O O O , or . OH Z1 is H Rk
8. The compound or therapeutically acceptable salt of claim 3, wherein O O O OH N , or . H Rk Z1 is
9. The compound or therapeutically acceptable salt of claim 2, wherein (11395927_1):GGG L1 is (CR6R7)q; and Y2 is selected from the group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, C5-6 heteroaryl, and C3-7 heterocycloalkyl; wherein R6 and R7, at each ence, are R15 or hydrogen; and q is 1, 2, or 3.
10. The compound or therapeutically acceptable salt of claim 3, wherein L1 is )q; and Y2 is selected from the group consisting of C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, C5-6 heteroaryl, and C3-7 heterocycloalkyl; wherein R6 and R7, at each occurrence, are R15 or hydrogen; and q is 1, 2, or 3.
11. The compound or therapeutically acceptable salt of claim 2, wherein L1 is selected from the group consisting of (CR6R7)s-C(O)NR6A-(CR6R7)r, and )s-S(O)2 NR6A-(CR6R7)r; s is 0; r is 0 or 1; R6A is independently selected from the group consisting of hydrogen, and C1-6 alkyl; and R6 and R7, at each occurrence, are hydrogen.
12. The compound or therapeutically acceptable salt of claim 3, wherein L1 is selected from the group consisting of )s-NR6AC(O)-(CR6R7)r, (CR6R7)s-C(O)NR6A-(CR6R7)r, (CR6R7)s-NR6A-(CR6R7)r, (CR6R7)s-S(O)2 NR6A -(CR6R7)r, and (CR6R7)s-NR6AS(O)2-(CR6R7)r; s is 0; r is 0 or 1; (11395927_1):GGG R6A is independently selected from the group consisting of hydrogen, and C1-6 alkyl; and R6 and R7, at each occurrence, are hydrogen.
13. A compound or a therapeutically acceptable salt thereof, wherein the compound has Formula (II), Formula (III), Formula (IV) or Formula (VI): Formula (II), Formula (III), Formula (IV), Formula (VI); wherein X is benzo[d]thiazolyl optionally substituted with one or two R4; Rx, at each occurrence, is independently selected from the group ting of R5, CO(O)R5, CO(O)H, CN, F, Cl, Br and I; L1 is selected from the group consisting of (CR6R7)q, (CR6R7)s-C(O)-(CR6R7)r, and (CR6R7)s-S(O)2-(CR6R7)r; and Y2 is selected from the group consisting of C3-11 branched chain alkyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, , and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, C4-7 cycloalkenyl, phenyl, and C3-7 heterocyclyl are optionally fused to one benzene ring; n Y2 is (11395927_1):GGG optionally substituted with one, two, or three substituents independently selected from the group consisting of R8, OR8, SO2R8, CO(O)R8, NHR8, N(R8)2, C(O)H, OH, CN, NO2, F, Cl, Br and I; or L1 is a bond; and Y2 is selected from the group consisting of C3-7 cycloalkyl, phenyl, and C3-7 heterocyclyl; wherein the C3-7 cycloalkyl, , and C3-7 heterocyclyl represented by Y2 are ally fused to one benzene ring; wherein each Y2 and each ring fused to Y2 are optionally substituted with one substituent independently selected from the group consisting of R8 and C(O)NHR8; Z1 is selected from the group consisting of R1 is absent; R2, at each occurrence, is independently C1-6 alkyl; R3 is absent; R4, at each occurrence, is ndently selected from the group consisting of OR12 and halogen; R5, at each occurrence, is independently ed from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, and cycloalkyl; R6 and R7, at each occurrence, are each independently selected from the group consisting of hydrogen, R15, and CO(O)R15; R8, at each occurrence, is independently selected from the group consisting of C1-6 alkyl, C2-6 alkynyl, aryl, heterocyclyl, and cycloalkyl; wherein the R8 C1-6 alkyl, and C2-6 alkynyl are optionally substituted with one, two, or three tuents independently selected from the group consisting of R16, OR16, , C(O)R16, N(R16)2, OH, F, Cl, Br and I; wherein the R8 aryl and heterocyclyl are optionally substituted with one substituent independently selected from the group consisting of C1-6 alkyl, F, Cl, Br and I; Rk, at each occurrence, is independently C1-6 alkyl; (11395927_1):GGG R12 is C1-4 alkyl; R15, at each occurrence, is independently selected from the group consisting of C1-4 alkyl, and aryl; wherein the R15 C1-4 alkyl is optionally substituted with one substituent independently selected from the group consisting C1-4 alkoxy, and heterocycloalkyl; R16, at each occurrence, is independently selected from the group consisting of C1-4 alkyl, aryl, heterocycloalkyl, and heteroaryl; q is 1, 2, or 3; s is 0; r is 0, or 1; m is 0; n is 0, or 1; o is 0, 1, or 2; and p is 0.
14. The compound or therapeutically acceptable salt of claim 1, n the compound is selected from the group ting of 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H- pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(pyridin ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(pyridin ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4- hydroxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(1- phenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{4-[2- (dimethylamino)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid; (11395927_1):GGG 3-(1-benzyl-1H-pyrazolyl){8-[(5,6-difluoro-1,3-benzothiazolyl)carbamoyl]-3,4- dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(4- fluorophenyl)ethyl]-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3- chlorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid; 3-(1-benzyl-1H-pyrazolyl){8-[(6-fluoro-1,3-benzothiazolyl)carbamoyl]-3,4- dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid; 3-(1-benzyl-1H-pyrazolyl){8-[(6-methoxy-1,3-benzothiazolyl)carbamoyl]-3,4- oisoquinolin-2(1H)-yl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-3,5- dimethyl-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3- methylbenzyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3- methoxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4- chlorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3- (benzyloxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3- hydroxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{3-[2- (dimethylamino)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl -1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl methyl-1H-pyrazolyl)pyridinecarboxylic acid; (11395927_1):GGG 3-(1-benzyl-1H-pyrazolyl){8-[(7-chloro-1,3-benzothiazolyl)carbamoyl]-3,4- dihydroisoquinolin-2(1H)-yl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[6-(pyrrolidin- 1-yl)pyridinyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-phenyl-1H- pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3- cyanobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid; 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2- chlorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(pyridin ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl cyano-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(naphthalen ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-(3-methyl- 1,2,4-oxadiazolyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-benzyl (hydroxymethyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2- (benzyloxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-methyl{[6- (pyrrolidinyl)pyridinyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-benzyl (ethoxycarbonyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3- (dimethylamino)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid; (11395927_1):GGG 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl carboxymethyl-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2- hydroxybenzyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,3-dihydro- 1H-indenyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2- phenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,4-dihydro- 2H-chromenyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[2- (dimethylamino)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2- fluorobenzyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1- (cyclohexylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1- (cyclohexylmethyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-{[3- hylamino)propyl]amino}nitrobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-fluoro nitrobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid; 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[2- (morpholinyl)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[3- (dimethylamino)propoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid; (11395927_1):GGG 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(pyridin ylmethoxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[2- (dimethylamino)ethoxy]benzyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(tetrahydro-2H- pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[3- (dimethylamino)propynyl]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,3- difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,5- difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,5- difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid; 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,6- difluorobenzyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(tetrahydro-2H- pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-nitrobenzyl)- 1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(biphenyl ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2,2- dimethylpropyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2- cyclohexylethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3- uoromethyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid; (11395927_1):GGG 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(biphenyl ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1- (cyclopentylmethyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3- formylbenzyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl phenyl-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl (tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1- phenylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{3- [(dimethylamino)methyl]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3- (methylsulfonyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1- (cyclohexylmethyl)cyclopropyl-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3,5-di-tertbutylbenzyl )-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(morpholin- lfonyl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(4,4- difluorocyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1- (trifluoromethyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1- (diphenylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; (11395927_1):GGG 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(morpholin- 4-yl)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[3-(morpholin- 4-yl)phenylpropyl]-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(tertbutoxycarbonyl idinyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-methyl{2-[2- (morpholinyl)ethoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2- (dimethylamino)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-methyl{2-[3- (morpholinyl)propoxy]benzyl}-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-methyl[(1- methylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[2-(4- chlorophenyl)-4,4-dimethylcyclohexenyl]methyl}-1H-pyrazolyl)pyridine carboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1- (cyclohexylmethyl)ethyl-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[(1R,2R,5R)- 6,6-dimethylbicyclo[3.1.1]heptyl]methyl}methyl-1H-pyrazolyl)pyridine carboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[(1S,2R,5S)- 6,6-dimethylbicyclo[3.1.1]heptyl]methyl}methyl-1H-pyrazolyl)pyridine carboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2- methylpropyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid; (11395927_1):GGG 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2- methoxyethyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid; 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(2- methoxyethoxy)benzyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2- methoxyethyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid; 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1R,2R,4R)- bicyclo[2.2.1]heptenylmethyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,3- dimethylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(3-methoxy phenylpropyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(4-methoxy phenylbutyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-methoxy oxophenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(2-cyclohexyl- 1-phenylethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(3- methoxypropyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{2-[3-hydroxy- 2-(hydroxymethyl)methylpropoxy]benzyl}methyl-1H-pyrazolyl)pyridine carboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-methyl[2- (tetrahydro-2H-pyranylmethoxy)benzyl]-1H-pyrazolyl}pyridinecarboxylic acid; (11395927_1):GGG 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[2-(1,4-dioxan- 2-ylmethoxy)benzyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2- methoxyethoxy)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid; 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](4- phenoxyphenyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](3- phenoxyphenyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-(4- nitrophenoxy)phenyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3-(4- chlorophenoxy)phenyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](3- benzylphenyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3- (cyclohexylmethyl)methylphenyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](4-methyl phenoxyphenyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-methyl phenoxyphenyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-methyl yphenyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-methyl phenoxyphenyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3- (cyclohexylmethoxy)methylphenyl]pyridinecarboxylic acid; (11395927_1):GGG 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][4- (cyclohexyloxy)methylphenyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3- (cyclohexyloxy)methylphenyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][4- (cyclohexylmethoxy)methylphenyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-cyano (cyclohexyloxy)phenyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-chloro (cyclohexyloxy)phenyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3- (cyclohexylamino)methylphenyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3- (cyclohexyloxy)fluorophenyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][3- (cyclohexyloxy)(trifluoromethyl)phenyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-[(3,3- dimethylcyclohexyl)oxy]methylphenyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H- 1,2,3-triazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-benzyl ycarbonyl)methyl-1H-pyrrolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl carboxymethyl-1H-pyrrolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H- yl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(4- methylphenyl)sulfonyl]-1H-pyrrolyl}pyridinecarboxylic acid; (11395927_1):GGG 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzoyl-1H- pyrrolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1- lsulfonyl)-1H-pyrrolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl cyanomethyl-1H-pyrrolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-cyano (cyclohexylmethyl)methyl-1H-pyrrolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano methyl{[1-(piperidinyl)cyclohexyl]methyl}-1H-pyrrolyl)pyridinecarboxylic acid; 6,6'-bis[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3,3'-bipyridine- 2,2'-dicarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-benzyl-1,2,3,4- ydroisoquinolinyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2- methoxyethyl)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(piperidin ylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2-(pyridin ylmethyl)-1,2,3,4-tetrahydroisoquinolinyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][2- (cyclohexylmethyl)-1,2,3,4-tetrahydroisoquinolinyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-(cyclohexyloxy)- 3'-methyl-3,4'-bipyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-(cyclohexyloxy)- 3,4'-bipyridinecarboxylic acid; (11395927_1):GGG 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'-phenoxy-3,4'- bipyridinecarboxylic acid; 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H- pyrrolo[2,3-b]pyridinyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-2'- phenoxy-3,4'-bipyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-2'- [methyl(phenyl)amino]-3,4'-bipyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1- (methoxymethyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid; 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3,3-dimethyl- 1-(morpholinyl)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2- methoxyethyl)-3,3-dimethylcyclohexyl]methyl}methyl-1H-pyrazolyl)pyridine carboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(3- methoxypropyl)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid; N-(1,3-benzothiazolyl){5-(1-{[1-(2-methoxyethyl)cycloheptyl]methyl}methyl-1H- pyrazolyl)[(methylsulfonyl)carbamoyl]pyridinyl}-1,2,3,4- tetrahydroisoquinolinecarboxamide; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(tetrahydro-2H- pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1- {[(1R,2R,3R,5S)(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]heptyl]methyl}-1H- pyrazolyl)pyridinecarboxylic acid; (11395927_1):GGG 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2- methoxyethoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[1-cyclohexyl- 3-(morpholinyl)propyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H- indazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl (tetrahydro-2H-pyranylmethyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl({1- rpholinyl)propoxy]cycloheptyl}methyl)-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-methyl [methyl(phenyl)amino]phenyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-methoxy- 3,3-dimethylcyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[(1S,2R,5S)- 6,6-dimethylbicyclo[3.1.1]heptyl]methyl}methyl-1H-1,2,3-triazolyl)pyridine carboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3-[(3,3- dimethylcyclohexyl)(methyl)amino]methylphenyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-methyl{[1- (morpholinyl)cyclohexyl]methyl}-1H-pyrazolyl)pyridinecarboxylic acid; 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2'- [cyclohexyl(methyl)amino]-3'-methyl-3,4'-bipyridinecarboxylic acid; N-(1,3-benzothiazolyl)(5-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]methyl- 1H-pyrazolyl}[(methylsulfonyl)carbamoyl]pyridinyl)-1,2,3,4- tetrahydroisoquinolinecarboxamide; (11395927_1):GGG 6-[8-(1,3-benzothiazolylcarbamoyl)methyl-3,4-dihydroisoquinolin-2(1H)-yl]{5- methyl[(1-methylcyclohexyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-cyano-2'- [cyclohexyl(methyl)amino]-3,4'-bipyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1- methoxycyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1-methoxy- 3,3-dimethylcyclohexyl)methyl]methyl-1H-1,2,3-triazolyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({1-[2-(1,1- dioxidothiomorpholinyl)ethoxy]cyclohexyl}methyl)methyl-1H-pyrazol yl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano methyl{[1-(morpholinyl)cyclohexyl]methyl}-1H-pyrrolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2- hydroxyethoxy)cyclohexyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2,3- dimethoxypropoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridine carboxylic acid; N-(1,3-benzothiazolyl){5-[5-cyano(cyclohexylmethyl)methyl-1H-pyrrolyl] [(methylsulfonyl)carbamoyl]pyridinyl}-1,2,3,4-tetrahydroisoquinoline amide; 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano{[1-(2- methoxyethoxy)cycloheptyl]methyl}methyl-1H-pyrrolyl)pyridinecarboxylic acid; (11395927_1):GGG 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(1,4- dioxanylmethoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridine carboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][5-methyl({1- rpholinyl)oxoethoxy]cyclohexyl}methyl)-1H-pyrazolyl]pyridine carboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2,3- oxypropoxy)cycloheptyl]methyl}methyl-1H-pyrazolyl)pyridine carboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](5-cyano{[1- (dimethylamino)cyclohexyl]methyl}methyl-1H-pyrrolyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{3- [(cyclohexylcarbonyl)(methyl)amino]methylphenyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,3-dimethyl- 1-[2-(methylsulfonyl)ethoxy]cyclohexyl}methyl)methyl-1H-pyrazolyl]pyridine carboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](2-methyl {methyl[(1-methylcyclohexyl)carbonyl]amino}phenyl)pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[1-(2- methoxyethoxy)-3,3-dimethylcyclohexyl]methyl}methyl-1H-pyrazolyl)pyridine carboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-cyano [(cyclohexylsulfonyl)(methyl)amino]phenyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{2-cyano[2- (tricyclo[3.3.1.13,7]decyl)pyrrolidinyl]phenyl}pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3'-methyl-2'- (piperidinyl)-3,4'-bipyridinecarboxylic acid; (11395927_1):GGG 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-(1-cyclohexyl- 3-methoxypropyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,3-dimethyl- 1-[2-(methylamino)ethoxy]cyclohexyl}methyl)methyl-1H-pyrazolyl]pyridine carboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{5-methyl [(2,6,6-trimethyltetrahydro-2H-pyranyl)methyl]-1H-pyrazolyl}pyridine carboxylic acid; 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H- indazolyl)pyridinecarboxylic acid; and 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-benzyl-1H- o[2,3-c]pyridinyl)pyridinecarboxylic acid.
15. A composition for treating bladder cancer, brain , breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, blastic leukemia, follicular ma, a lymphoid malignancy of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen cancer, said composition comprising an excipient and a therapeutically effective amount of the compound or therapeutically acceptable salt of claim 1.
16. Use of a compound or therapeutically acceptable salt of any one of claims 1-14 in the manufacture of a medicament for treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic cytic ia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, a lymphoid ancy of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen . (11395927_1):GGG
17. Use of a compound or therapeutically acceptable salt of any one of claims 1-14 and one additional therapeutic agent in the manufacture of a ment for treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular , lymphoblastic leukemia, follicular lymphoma, a lymphoid malignancy of T-cell or B-cell , ma, enous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen cancer.
18. 6-[8-(1,3-Benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(1- methoxy-3,3-dimethylcyclohexyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid or a therapeutically acceptable salt thereof.
19. A composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4- dihydroisoquinolin-2(1H)-yl]{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]methyl- 1H-pyrazolyl}pyridinecarboxylic acid or a therapeutically acceptable salt thereof.
20. Use of a compound or therapeutically acceptable salt of claim 18 in the manufacture of a medicament for treating bladder , brain cancer, breast cancer, bone marrow cancer, cervical cancer, c lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, a lymphoid malignancy of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral , ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen .
21. A method of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, al cancer, chronic lymphocytic leukemia, colorectal cancer, geal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, a lymphoid ancy (11395927_1):GGG of T-cell or B-cell origin, melanoma, enous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer or spleen cancer in a non-human patient, the method comprising administering to the patient a therapeutically effective amount of a compound or therapeutically acceptable salt of any one of claims 1 – 14.
22. A method of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal , hepatocellular cancer, lymphoblastic leukemia, follicular ma, a lymphoid malignancy of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral , ovarian cancer, non-small cell lung , te cancer, small cell lung cancer or spleen cancer in a non-human patient, the method comprising administering to the patient a therapeutically effective amount of 6-[8-(1,3-Benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]- 3-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]methyl-1H-pyrazolyl}pyridine carboxylic acid or a therapeutically acceptable salt thereof.
23. The method ing to claim 21 or 22 wherein said method further comprises administering to said patient one additional therapeutic agent.
Applications Claiming Priority (5)
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US201161547165P | 2011-10-14 | 2011-10-14 | |
US61/547,165 | 2011-10-14 | ||
CNPCT/CN2012/078372 | 2012-07-09 | ||
CN2012078372 | 2012-07-09 | ||
PCT/US2012/059717 WO2013055895A1 (en) | 2011-10-14 | 2012-10-11 | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
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NZ623068A NZ623068A (en) | 2016-07-29 |
NZ623068B2 true NZ623068B2 (en) | 2016-11-01 |
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