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3-methylpyridazine
1. Pyrazoles as casein kinase 1 delta modulators and their preparation
By Lebold, Terry Patrick; McCarver, Stefan; Mcclure, Kelly J.; Preville, Cathy; Seierstad, Mark; Shireman, Brock T.;
Wu, Dongpei; Zhang, Wei; Wang, Jocelyn; Ziff, Jeannie
From PCT Int. Appl. (2022), WO 2022058921 A1 20220324, Language: English, Database: CAPLUS
A compd. of formula I or pharmaceutical compns. contg. them, methods of making them, and methods of using them
including methods for treating disease states, disorders, and conditions assocd. with casein kinase 1 delta (CSNK1D)
modulation, such as those assocd. with mood/psychiatric disorders, and neurodegenerative diseases. Compds. of
formula I wherein R1 is 5-membered heteroaryl, substituted pyridinyl, (un)substituted pyrimidinyl, (un)substituted
pyrazinyl, etc.; R2 is 2-(acylamino)pyridin-4-yl, (un)substituted pyrrolopyridinyl, (un)substituted pyrazolylpyridinyl, etc.; R3
is C1-6 alkyl, CH2CH2OCH3, C1-6 haloalkyl, C3-6 cycloalkyl, etc.; R4 is H, C1-3 alkyl, and C3-6 cycloalkyl; and
pharmaceutically acceptable salts, N-oxides or solvates thereof, are claimed. Example compd. II was prepd. by cross-
coupling of 2- (3-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-hydroxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-uide
lithium salt with 4-bromopyridin-2-amine; the resulting 4-(3-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)pyridin-2-amine
underwent N-acylation with propionic acid to give compd. II. The invention compds. were evaluated for their CSNK1D
modulatory activity. From the assay, it was detd. that compd. II exhibited an IC50 value of 0.107 µM and an AC50 value
of 0.005 µM.

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2. Indazoles and azaindazoles as LRRK2 inhibitors in the treatment of CNS disorders and their preparation
By Garofalo, Albert W.; De Lombaert, Stephane; Schwarz, Jacob Bradley; Andreotti, Daniele; Sabbatini, Fabio Maria;
Serra, Elena; Bernardi, Silvia; Migliore, Marco; Budassi, Federica; Beato, Claudia
From PCT Int. Appl. (2021), WO 2021007477 A1 20210114, Language: English, Database: CAPLUS
The invention relates compds. of formula I, their prepn. and their use as inhibitors of LRRK2 in the treatment of CNS
disorders. Compd. I, wherein A is halo, (un)subsititued C1-6 alkyl, (un)subsititued C2-6 alkenyl, etc.; ring B is Ph and 5- to
10-membered heteroaryl wherein said 5- to 10-membered heteroaryl comprises 1, 2 and 3 ring-forming heteroatoms
independently864 selected from N, O and S; X2 is N and CR2; X3 is N and CR3; X4 is N and CR4; no more than two of
X2, X3 and X4 are simultaneously N; R1 is independently H, halo, C1-6 alkyl, etc.; R2 and R4 are independently H, halo,
C2-6 alkenyl, etc.; R3 is H, halo, C1-6 haloalkyl, etc.; n is 0, 1, 2, and 3; and pharmaceutically acceptable salts thereof, are
claimed. Compd. II was prepd. by reacting 3-bromo-1H-indazol-5-amine with 3-furanylboronic acid yielding 3-(furan-3-
yl)-1H-indazole-5-amine, then 5-cyano-3-fluoropyridine-2-carboxylic acid underwent amidation with 3-(furan-3-yl)-1H-
indazole-5-amine to yield compd. II. Compd. II was evaluated for LRRK2 inhibitory activity resulting in a wild type LRRK2
and G2019S LRRK2 IC50 of ≤ 100 nM for both. Compds. of the invention were evaluated for their LRRK2 inhibitory
activity (data given).
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3. Cyclohexenone derivatives as small molecule modulators of the BTB domain of KEAP1 and their preparation,
pharmaceutical compositions and use in the treatment of diseases
By Bartholomeus, Johan; Buerli, Roland; Jarvis, Rebecca; Johnstone, Shawn; Ostenfeld, Thor; Terstiege, Ina;
Travagli, Massimiliano; Turcotte, Stephane
From PCT Int. Appl. (2019), WO 2019122265 A1 20190627, Language: English, Database: CAPLUS
The application relates to Cyclohexenone derivs. of formula I and their pharmaceutical compns./prepns. This application
further relates to the methods of treating or preventing neurodegenerative disorders, such as Alzheimer's disease (AD),
Parkinson's disease (PD), Huntington disease (HD) and other CAG-triplet repeat (or polyglutamine) diseases,
amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), diffuse Lewy body disease, chorea-acanthocytosis, primary
lateral sclerosis, multiple sclerosis (MS), frontotemporal dementia, Friedreich's ataxia, acute head injury, and epilepsy
(repression of microglia activation). Compds. of formula I wherein X is CO, SO2; R1 and R2 are independently H, C1-6
alkyl; R1R2 may be taken together with the carbon atom attached to form spirocycloalkyl ring, spiroheterocycloalkyl ring;
R3 is OH, (un)substituted alkoxy; R4 is (un)substituted alkoxy, (un)substituted heteroaryl; and their pharmaceutically
acceptable salts as small mol. modulators of the BTB domain of KEAP1 in the treatment of diseases thereof, are
claimed. Example compd. II was prepd. by using nucleophilic addn., O-methylation, ring-enlargement, and
dehydrogenation as the key steps. All the invention compds. were evaluated for their BTB domain of KEAP1 modulating
activity.
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4. Preparation of pyridazinyl benzimidazoles and related nitrogen heterocycles as metalloenzyme inhibitors for
the treatment of diseases
By Sparks, Steven; Yates, Christopher M.; Shaver, Sammy R.; Hoekstra, William J.
From PCT Int. Appl. (2018), WO 2018125800 A2 20180705, Language: English, Database: CAPLUS
The invention relates to prepn. of pyridazinyl benzimidazoles of formula I as metalloenzyme inhibitors. Compds. I
wherein A is N or CR5; W, X, Y, Z each independently is N or CR6; R1, R2 and R3 each independently is H, halo, CN,
etc.; R4 is alkyl, cycloalkyl, haloalkyl, etc., are claimed. The example compd. II was prepd. by multistep procedure
(procedure given). Compds. I were evaluated for their biol. activity as metalloenzyme inhibitors (data given). Compds. I
have metalloenzyme modulating activity, and can be useful in treatment of diseases, disorders or symptoms thereof
mediated by such metalloenzymes.
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5. Preparation of active compounds for preventing and treating cervicitis

By Miao, Hui; Zhao, Wanxin; Ai, Hengling; Ma, Li; Ge, Weihan; Tan, Ziqiang
From Faming Zhuanli Shenqing (2017), CN 107445981 A 20171208, Language: Chinese, Database: CAPLUS
The title compds. I [wherein M = N or CR; R, R1 and R2 = independently H, halo, alkyl, NO2, OH, etc.; R3 = H, alkyl, or
(un)substituted cycloalkyl; L = a bond or C1-6 alkylene], their pharmaceutically acceptable salts, tautomers, optical
isomers, solvates, and prodrugs were prepd. as Btk inhibitors for preventing and treating inflammatory diseases such as
cervicitis. For example, II was prepd. in a multi-step synthesis. The title compds. showed inhibitory activity with IC50 of
7.9-25.3 nM against Btk.
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3-methylpyridazine

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6. Biaryl compounds as kinase inhibitors and their preparation

By Bronson, Joanne J.; Chen, Ling; Ditta, Jonathan L.; Dzierba, Carolyn Diane; Jalagam, Prasada Rao; Luo, Guanglin;
Macor, John E.; Maishal, Tarun Kumar; Nara, Susheel Jethanand; Rajamani, Ramkumar; et al
From PCT Int. Appl. (2017), WO 2017059085 A1 20170406, Language: English, Database: CAPLUS
The disclosure is directed to biaryl compds. which can inhibit
AAK1 (adaptor assocd. kinase 1), compns. comprising such
compds. and their use for treating e.g. pain, Alzheimer's
disease, Parkinson's disease and schizophrenia. Example
compd. I was prepd. by acetylation of 4-bromopyridin-2-amine
with acetyl chloride; the resulting N-(4-bromopyridin-2-
yl)acetamide underwent cross-coupling with (3-fluoro-4-
hydroxyphenyl)boronic acid to give N-(4-(3-fluoro-4-
hydroxyphenyl)pyridin-2-yl)acetamide, which underwent
etherification with (S)-2-(1-hydroxy-4-methylpentan-2-
yl)isoindoline-1,3-dione, which underwent hydrolysis to give
compd. I. The invention compds. were evaluated for their
AAK1 inhibitory activity. From the assay, it was detd. that
compd. II exhibited IC50 value of 2.7 nM.
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7. Preparation of biaryl compounds as kinase inhibitors

By Luo, Guanglin; Chen, Ling; Dzierba, Carolyn Diane; Ditta, Jonathan L.; Macor, John E.; Bronson, Joanne J.
From PCT Int. Appl. (2015), WO 2015153720 A1 20151008, Language: English, Database: CAPLUS
The present invention provides biaryl compds. I [A = O, P, Q,
etc.; B = W, X, Y, etc.; R1 = H, amino, CO2H, etc.; R2 = H, CN,
CH2OH, etc.; R3 = H, CN, cyclopropyl, etc.; R4 = H, halo or
methyl; R5 = M1, M2 or M3; R6 = H, Et, fluoromethyl, etc.; R7 =
methyl] as kinase inhibitors. For example, compd. II was
subjected to coupling with N-[4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)pyridin-2-yl]acetamide followed by cleavage
of the Boc group to provide compd. III. Compd. III exhibited
inhibitory activity against AAK1 (adaptor assocd. kinase 1) with
an IC50 value of 2.7 nM. The invention compds. are useful for
the treatment of diseases mediated by AAK1 activity such as
Alzheimer's disease, bipolar disorder, pain, etc.
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8. 2-(Benzothiazol-2-yl)-2-sulfonylacetamides as inhibitors of endothelial lipase and their preparation

By Johnson, James A.; Pi, Zulan; Qiao, Jennifer X.; Kim, Soong-Hoon; Wang, Tammy C.; Jiang, Ji; Finlay, Heather;
Lloyd, John
From PCT Int. Appl. (2015), WO 2015105749 A1 20150716, Language: English, Database: CAPLUS
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3-methylpyridazine
The invention provides compds. of formula I and compns.
comprising any of such compds. These compds. are
endothelial lipase (EL) inhibitors which may be used
medicaments. Compds. of formula I wherein R1 is halo, CN,
acyl, etc.; R2 is independently halo, OH, C1-4 alkyl, C1-4 alkoxy,
etc.; R3 is (un)substituted C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl,
etc.; R4 is (CH2)1-3CONHR5; R5 is (un)substituted C1-6 alkyl, 4-
to 6-membered heterocyclyl-(CH2)0-3 and (un)substituted C3-6
carbocyclyl-(CH2)0-3; and stereoisomers, tautomers and
pharmaceutically acceptable salts thereof, are claimed.
Example compd. II was prepd. by a multistep procedure
(procedure given). The invention compds. were evaluated for
their endothelial lipase inhibitory activity. From the assay, it
was detd. that compd. II exhibited and IC50 value of 3 nM.

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9. Preparation of heterocyclic compounds as BRD4 inhibitors and uses thereof

By Zhang, Jiazhong; Buell, John; Chan, Katrina; Ibrahim, Prabha N.; Lin, Jack; Pham, Phuongly; Shi, Songyuan;
Spevak, Wayne; Wu, Guoxian; Wu, Jeffrey
From PCT Int. Appl. (2014), WO 2014145051 A1 20140918, Language: English, Database: CAPLUS
The invention relates to heterocyclic compds. of formula I as BRD4 inhibitors, methods for their prepn., pharmaceutical
compns. contg. such a compd. and their therapeutic uses for treating cancer, autoimmune and inflammatory conditions.
Compds. of formula I wherein Y2 is N and Y3 is C; or Y2 is C and Y3 is N; Y1 is CH and N; L is a bond, (un)substituted C1-
1 2 4 3 5
6 alkylene, CO, SO2, etc.; R , R , R are independently H, D, (un)substituted C1-6 alkyl, etc.; R is H, halo, CN, etc.; R is
(un)substituted 5- to 6-membered heteroaryl, (un)substituted heterocycloalkyl; and pharmaceutically acceptable salts,
prodrugs, solvates, tautomers, isomers and deuterated analogs thereof, are claimed. Example compd. II was prepd. by
cross-coupling of 6-bromo-2-methyl-1H-pyrrolo[3,2-b]pyridine with 3,5-dimethylisoxazol-4-ylboronic acid. The invention
compds. were evaluated for their BRD4 inhibitory activity. From the assay, it was detd. that example compd. II exhibited
IC50 value ranged from 1 µM to 10 µM.
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10. Preparation of nitrogen-containing heterocyclic compounds as muscarinic M1 receptor positive allosteric

modulators
By Sugimoto, Takahiro; Nakamura, Minoru; Sakamoto, Hiroki; Suzuki, Shinkichi; Yamada, Masami; Kamata, Makoto;
Kojima, Takuto; Fujimori, Ikuo; Shimokawa, Kenichiro
From PCT Int. Appl. (2014), WO 2014077401 A1 20140522, Language: Japanese, Database: CAPLUS
Provided is a compd. that has cholinergic muscarinic M1
receptor pos. allosteric modulator activity and that is useful in
the prevention and treatment of conditions such as Alzheimer's
disease, schizophrenia, pain, and sleep disorders. The present
invention relates to a compd. represented by formula (I) or to a
salt of the same, wherein the formula, ring A represents an
optionally substituted 4-7 membered ring; L represents -O-, -S-,
-SO- or -SO2-; R1 represents an optionally substituted C1-6
alkyl group (if L is -O-, a C1-6 alkyl group optionally substituted
by a halogen is excluded) or an optionally substituted cyclic
group; X1 represents -CRa= or -N=; X2 represents -CRb= or -
N=; X3 represents -CRc= or -N=; and Ra, Rb and Rc represent
H, halogen, or an optionally substituted C1-6 alkyl group, C2-6
alkenyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C3-6
cycloalkoxy group or C6-14 aryl group. Thus, 7-[(trans-2-
hydroxycyclohexyl)oxy]-2-[4-(1-methyl-1H-pyrazol-4-
yl)benzyl]isoindolin-1-one (prepn. given) showed 102%
cholinergic muscarine M1 receptor pos. allosteric modulator
activity at 10 µM.

~5 Citings

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