JPWO2022099071A5

JPWO2022099071A5 -

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Publication number: JPWO2022099071A5
Application number: JP2023526986A
Authority: JP
Publication date: 2024-11-13

Description

本明細書に記載されるものに加えて、本発明の種々の修正形態が上述の説明から当業者に明らかとなろう。かかる修正形態もまた、添付の特許請求の範囲内に該当することが意図される。本願に引用される全ての特許、特許出願、及び刊行物を含めた各参考文献は、参照によりその全体が本明細書に援用される。
本願は下記の態様も包含する。
［態様１］
式１の化合物またはその薬学的に許容される塩の結晶形態：
［態様２］
前記式１の化合物または前記その薬学的に許容される塩が、前記式１の化合物の遊離塩基である、態様１に記載の結晶形態。
［態様３］
前記式１の化合物の前記遊離塩基が、セスキ水和物である、態様２に記載の結晶形態。
［態様４］
形態Ｉを有する、態様２または３に記載の結晶形態。
［態様５］
２シータ（±０．２度）で、７．０、８．５、１０．０、１０．６、１４．６、１５．２、１５．８、１７．２、２０．１、２１．１、２３．９、２４．８、２６．１、２８．１、２９．６、及び３０．２度から選択される少なくとも１つのＸＲＰＤピークを有する、態様４に記載の結晶形態。
［態様６］
２シータ（±０．２度）で、７．０、８．５、１０．０、１０．６、１４．６、１５．２、１５．８、１７．２、２０．１、２１．１、２３．９、２４．８、２６．１、２８．１、２９．６、及び３０．２度から選択される少なくとも４つのＸＲＰＤピークを有する、態様４に記載の結晶形態。
［態様７］
ＤＳＣサーモグラムにおいて、開始温度（±３℃）が３５℃及び最高温度（±３℃）が６８℃、ならびに開始温度（±３℃）が１６１℃及び最高温度（±３℃）が１６９℃の２つの吸熱ピークを有する、態様４～６のいずれか１つに記載の結晶形態。
［態様８］
形態ＩＩを有する、態様２に記載の結晶形態。
［態様９］
２シータ（±０．２度）で、８．５、１５．０、１５．７、１７．０、１８．６、２０．２、２０．５、２１．７、２５．５、及び２６．７度から選択される少なくとも４つのＸＲＰＤピークを有する、態様８に記載の結晶形態。
［態様１０］
ＤＳＣサーモグラムにおいて、最高温度（±３℃）が７６℃、開始温度（±３℃）が１６５℃及び最高温度（±３℃）が１７３℃、開始温度（±３℃）が２０６℃及び最高温度（±３℃）が２２４℃の３つの吸熱ピークを有する、態様８または９に記載の結晶形態。
［態様１１］
前記式１の化合物または前記その薬学的に許容される塩が、メタンスルホン酸塩である、態様１に記載の結晶形態。
［態様１２］
形態ＩＩＩを有する、態様１１に記載の結晶形態。
［態様１３］
２シータ（±０．２度）で、５．２、７．５、８．２、８．８、９．４、１１．６、１２．４、１３．０、１４．０、１４．８、１５．８、１６．６、１６．９、１７．３、１７．９、１９．２、２３．６、２４．５、２５．５、及び２６．６度から選択される少なくとも４つのＸＲＰＤピークを有する、態様１１または１２に記載の結晶形態。
［態様１４］
ＤＳＣサーモグラムにおいて、開始温度（±３℃）が３０℃及び最高温度（±３℃）が６７℃、開始温度（±３℃）が１７９℃及び最高温度（±３℃）が２０２℃の２つの吸熱ピークを有する、態様１１～１３のいずれか１つに記載の結晶形態。
［態様１５］
（Ｒ）－１－（（７－シアノ－２－（３’－（（２－（ジフルオロメチル）－７－（（３－ヒドロキシピロリジン－１－イル）メチル）ピリド［３，２－ｄ］ピリミジン－４－イル）アミノ）－２，２’－ジメチル－［１，１’－ビフェニル］－３－イル）ベンゾ［ｄ］オキサゾール－５－イル）メチル）ピペリジン－４－カルボン酸（式１の化合物）、またはその塩を調製するプロセスであって、
式Ｂ－２の化合物：
またはその塩を、式Ｂ－３の塩：
（式中、Ｍ ^＋は、Ｌｉ ^＋、Ｎａ ^＋、Ｋ ^＋、またはＣｓ ^＋である）と、鈴木触媒及び塩基の存在下で反応させて、式Ａ－７の化合物：
またはその塩を形成させることを含み、式中、Ｒ ^１が、Ｃ _１－６アルキルであり、Ｘ ^１ｂが、ハロである、前記プロセス。
［態様１６］
Ｘ ^１ｂが、ブロモである、態様１５に記載のプロセス。
［態様１７］
前記鈴木触媒が、パラジウム触媒である、態様１５または１６に記載のプロセス。
［態様１８］
前記式Ｂ－２の化合物または前記その塩と、前記式Ｂ－３の塩との前記反応に存在する前記塩基が、アルカリ金属炭酸塩である、態様１５～１７のいずれか１つに記載のプロセス。
［態様１９］
前記プロセスが、
式Ｂ－２ａの化合物：
またはその塩を、式Ｂ－３ａの塩：
と、鈴木触媒及び塩基の存在下で反応させて、式Ａ－７ａの化合物：
またはその塩を形成させることを含む、態様１５に記載のプロセス。
［態様２０］
前記プロセスが、
式Ｂ－２ａ’の化合物：
またはその塩を、式Ｂ－３ａの塩：
と、鈴木触媒及び塩基の存在下で反応させて、式Ａ－７ａ’の化合物：
またはその塩を形成させることを含む、態様１５に記載のプロセス。
［態様２１］
（Ｒ）－１－（（７－シアノ－２－（３’－（（２－（ジフルオロメチル）－７－（（３－ヒドロキシピロリジン－１－イル）メチル）ピリド［３，２－ｄ］ピリミジン－４－イル）アミノ）－２，２’－ジメチル－［１，１’－ビフェニル］－３－イル）ベンゾ［ｄ］オキサゾール－５－イル）メチル）ピペリジン－４－カルボン酸（式１の化合物）、またはその塩を調製するプロセスであって、
式Ａ－３の化合物：
またはその塩を、式Ｂ－１の化合物：
またはその塩と、塩基の存在下で反応させて、式Ｂ－２の化合物：
またはその塩を形成させることを含み、式中、Ｒ ^１が、Ｃ _１－６アルキルであり、Ｘ ^１ｂ及びＸ ^２ｂが独立して、ハロである、前記プロセス。
［態様２２］
前記式Ａ－３の化合物または前記その塩と、前記式Ｂ－１の化合物または前記その塩との前記反応に存在する前記塩基が、アルカリ金属炭酸塩である、態様２１に記載のプロセス。
［態様２３］
Ｘ ^１ｂが、ブロモまたはクロロである、態様２１または２２に記載のプロセス。
［態様２４］
前記プロセスが、
式Ｂ－２の化合物：
またはその塩を、式Ｂ－３の塩：
（式中、Ｍ ^＋は、Ｌｉ ^＋、Ｎａ ^＋、Ｋ ^＋、またはＣｓ ^＋である）と、鈴木触媒及び塩基の存在下で反応させて、式Ａ－７の化合物：
またはその塩を形成させることをさらに含み、式中、Ｒ ^１が、Ｃ _１－６アルキルであり、Ｘ ^１ｂが、ハロである、態様２１～２３のいずれか１つに記載のプロセス。
［態様２５］
前記プロセスが、
式Ａ－３ａの化合物：
またはその塩を、式Ｂ－１ａの化合物：
またはその塩と、塩基の存在下で反応させて、式Ｂ－２ａの化合物：
またはその塩を形成させることを含む、態様２１に記載のプロセス。
［態様２６］
前記プロセスが、
式Ａ－３ａ’の化合物：
またはその塩を、式Ｂ－１ａの化合物：
またはその塩と、塩基の存在下で反応させて、式Ｂ－２ａ’の化合物：
またはその塩を形成させることを含む、態様２１に記載のプロセス。
［態様２７］
（Ｒ）－１－（（７－シアノ－２－（３’－（（２－（ジフルオロメチル）－７－（（３－ヒドロキシピロリジン－１－イル）メチル）ピリド［３，２－ｄ］ピリミジン－４－イル）アミノ）－２，２’－ジメチル－［１，１’－ビフェニル］－３－イル）ベンゾ［ｄ］オキサゾール－５－イル）メチル）ピペリジン－４－カルボン酸（式１の化合物）、またはその塩を調製するプロセスであって、
式Ａ－３の化合物：
またはその塩を、式Ａ－４の化合物：
またはその塩と反応させて、式Ａ－５の化合物：
またはその塩を形成させることを含み、式中、Ｒ ^１が、Ｃ _１－６アルキルであり、Ｘ ^２ａが、ハロである、前記プロセス。
［態様２８］
前記式Ａ－３の化合物または前記その塩と、前記式Ａ－４の化合物または前記その塩との前記反応が、ハロゲン化アルカリ金属及び塩基の存在下で実施される、態様２７に記載のプロセス。
［態様２９］
前記ハロゲン化アルカリ金属が、臭化アルカリ金属である、態様２８に記載のプロセス。
［態様３０］
前記ハロゲン化アルカリ金属が、ＬｉＢｒである、態様２８または２９に記載のプロセス。
［態様３１］
前記塩基が、第三級アミンである、態様２８～３０のいずれか１つに記載のプロセス。
［態様３２］
前記塩基が、Ｎ，Ｎ－ジイソプロピルアミン、メチルアミン、ジメチルアミン、トリメチルアミン、及びエチルアミンから選択される、態様２８～３１のいずれか１つに記載のプロセス。
［態様３３］
前記プロセスが、
式Ａ－３ａの化合物：
またはその塩を、式Ａ－４ａの化合物：
またはその塩と、ハロゲン化アルカリ金属及び塩基の存在下で反応させて、式Ａ－５ａの化合物：
またはその塩を形成させることを含む、態様２７に記載のプロセス。
［態様３４］
前記プロセスが、
ａ）式Ａ－３ａの化合物：
またはその塩を、式Ａ－４ａの化合物：
またはその塩と、ハロゲン化アルカリ金属及び塩基の存在下で反応させて、式Ａ－５ａの化合物：
またはその塩を形成させることと、
ｂ）前記式Ａ－５ａの化合物：
またはその塩を、式Ａ－６の化合物：
またはその塩と、還元剤の存在下で反応させて、式Ａ－７ａの化合物：
またはその塩を形成させることと、
ｃ）前記式Ａ－７ａの化合物：
またはその塩をルイス酸と反応させて、前記式１の化合物：
またはその塩を形成させることと、を含む、態様２７に記載のプロセス。
［態様３５］
（Ｒ）－１－（（７－シアノ－２－（３’－（（２－（ジフルオロメチル）－７－（（３－ヒドロキシピロリジン－１－イル）メチル）ピリド［３，２－ｄ］ピリミジン－４－イル）アミノ）－２，２’－ジメチル－［１，１’－ビフェニル］－３－イル）ベンゾ［ｄ］オキサゾール－５－イル）メチル）ピペリジン－４－カルボン酸（式１の化合物）、またはその塩を調製するプロセスであって、
式Ａ－５の化合物：
またはその塩を、式Ａ－６の化合物：
またはその塩と、還元剤の存在下で反応させて、式Ａ－７の化合物：
またはその塩を形成させることを含み、式中、Ｒ ^１が、Ｃ _１－６アルキルである、前記プロセス。
［態様３６］
前記プロセスが、
式Ａ－５の化合物：
またはその塩を、式Ａ－６の化合物：
またはその塩と、還元剤の存在下で反応させて、式Ａ－７の化合物：
またはその塩を形成させることをさらに含み、式中、Ｒ ^１が、Ｃ _１－６アルキルである、態様２７～３２のいずれか１つに記載のプロセス。
［態様３７］
前記還元剤が、水素化ホウ素還元剤である、態様３５または３６に記載のプロセス。
［態様３８］
前記還元剤が、ＮａＢＨ _４、ＮａＢＨ _３ＣＮ、及びＮａＢＨ（ＯＡｃ） _３から選択される、態様３５～３７のいずれか１つに記載のプロセス。
［態様３９］
前記式Ａ－５の化合物または前記その塩と、前記式Ａ－６の化合物または前記その塩との前記反応が、触媒の存在下で実行される、態様３５～３８のいずれか１つに記載のプロセス。
［態様４０］
前記触媒が、ホウ酸トリメチルである、態様３９に記載のプロセス。
［態様４１］
前記式Ａ－５の化合物または前記その塩と、前記式Ａ－６の化合物またはその塩との前記反応が、有機ニトリル及び有機ハロゲン化物を含む溶媒成分中で実行される、態様３５～４０のいずれか１つに記載のプロセス。
［態様４２］
前記プロセスが、
式Ａ－５ａの化合物：
またはその塩を、式Ａ－６の化合物：
またはその塩と、還元剤の存在下で反応させて、式Ａ－７ａの化合物：
またはその塩を形成させることを含む、態様３５または３６に記載のプロセス。
［態様４３］
前記式Ａ－３の化合物または前記その塩が、
式Ａ－１の化合物：
またはその塩を、式Ａ－２の化合物：
またはその塩と、鈴木触媒及び塩基の存在下で反応させることを含むプロセスによって調製され、式中、
Ｘ ^３ａが、ハロであり、
Ｒ ^１が、Ｃ _１－６アルキルであり、
各Ｒ ^２が独立して、Ｈ及びＣ _１－６アルキルから選択されるか、または
各Ｒ ^２が一緒に、任意選択で１、２、３、もしくは４つの独立して選択されるＣ _１－４アルキル基により置換される、Ｃ _２－３アルキレンリンカーを形成する、態様２１～２４及び２７～３２のいずれか１つに記載のプロセス。
［態様４４］
前記プロセスが、
式Ａ－１ａの化合物：
またはその塩を、式Ａ－２ａの化合物：
またはその塩と、鈴木触媒及び塩基の存在下で反応させることを含む、態様４３に記載のプロセス。
［態様４５］
前記プロセスが、
式Ａ－１ａ’の化合物：
またはその塩を、式Ａ－２ａの化合物：
またはその塩と、鈴木触媒及び塩基の存在下で反応させることを含む、態様４３に記載のプロセス。
［態様４６］
前記式１の化合物または前記その塩が、
式Ａ－７の化合物：
またはその塩を前記式１の化合物：
またはその塩に変換することを含むプロセスによって調製され、式中、Ｒ ^１が、Ｃ _１－６アルキルである、態様１５～１８、２４、及び３５～４１のいずれか１つに記載のプロセス。
［態様４７］
前記式Ａ－７の化合物または前記その塩から、前記式１の化合物または前記その塩への前記変換が、前記式Ａ－７の化合物または前記その塩をルイス酸で処理することを含む、態様４６に記載のプロセス。
［態様４８］
前記式Ａ－７の化合物または前記その塩の前記変換に存在する前記ルイス酸が、ヨードトリメチルシランである、態様４７に記載のプロセス。
［態様４９］
前記式Ａ－７の化合物または前記その塩から、前記式１の化合物または前記その塩への前記変換が、前記式Ａ－７の化合物または前記その塩を塩基で処理することを含む、態様４６に記載のプロセス。
［態様５０］
前記式Ａ－７の化合物または前記その塩の前記変換に存在する前記塩基が、水酸化ナトリウムである、態様４７に記載のプロセス。
［態様５１］
前記式１の化合物または前記その塩が、
式Ａ－７ａの化合物：
またはその塩をルイス酸と反応させて、前記式１の化合物：
またはその塩を形成させることを含むプロセスによって調製される、態様４６～４８のいずれか１つに記載のプロセス。
［態様５２］
前記式１の化合物または前記その塩が、
式Ａ－７ａ’の化合物：
またはその塩を塩基と反応させて、前記式１の化合物：
またはその塩を形成させることを含むプロセスによって調製される、態様４６及び４９～５０のいずれか１つに記載のプロセス。
［態様５３］
式Ａ－１の化合物：
またはその塩を調製するプロセスであって、式６の化合物：
またはその塩を酸化条件下で変換して、前記式Ａ－１の化合物または前記その塩を形成させることを含み、式中、Ｒ ^１が、Ｃ _１－６アルキルであり、Ｘ ^３ａが、ハロである、前記プロセス。
［態様５４］
前記式６の化合物または前記その塩が、
式５の化合物：
またはその塩を、式９の化合物：
またはその塩と反応させることを含むプロセスによって調製され、式中、Ｒ ^１が、Ｃ _１－６アルキル、及びパラホルムアルデヒドであり、Ｘ ^３ａが、ハロである、態様５３に記載のプロセス。
［態様５５］
前記式５の化合物または前記その塩が、
式４の化合物：
を前記式５の化合物またはその塩に加水分解することを含むプロセスによって調製され、式中、Ｘ ^３ａが、ハロである、態様５４に記載のプロセス。
［態様５６］
前記式４の化合物が、
式３の化合物：
またはその塩を、式８Ａの化合物：
と、塩基の存在下で反応させることを含むプロセスによって調製され、式中、Ｘ ^３ａが、ハロである、態様５５に記載のプロセス。
［態様５７］
前記式８Ａの化合物が、
式８の化合物：
またはその塩を塩素化剤と反応させることを含むプロセスによって調製され、式中、Ｘ ^３ａが、ハロである、態様５６に記載のプロセス。
［態様５８］
Ｘ ^３ａが、ブロモである、態様５３～５７のいずれか１つに記載のプロセス。
［態様５９］
Ｒ ^１が、ｔ－ブチルである、態様５３～５８のいずれか１つに記載のプロセス。
［態様６０］
前記式Ｂ－１の化合物または前記その塩が、
式１２の化合物：
またはその塩をハロゲン化剤と反応させることを含むプロセスによって調製され、式中、Ｘ ^１ｂが、ハロである、態様３１～３３のいずれか１つに記載のプロセス。
［態様６１］
Ｘ ^１ｂが、ブロモである、態様６０に記載のプロセス。
［態様６２］
前記ハロゲン化剤が、塩素化剤である、態様６０または６１に記載のプロセス。
［態様６３］
前記式Ａ－４の化合物または前記その塩が、
式１４の化合物：
またはその塩を酸化して、前記式Ａ－４の化合物を形成させることを含むプロセスによって調製され、式中、Ｘ ^２ａが、ハロである、態様２７～３２のいずれか１つに記載のプロセス。
［態様６４］
Ｘ ^２ａが、クロロである、態様６３に記載のプロセス。
［態様６５］
前記式１４の化合物または前記その塩が、
式１３の化合物：
またはその塩をハロゲン化剤と反応させて、前記式１４の化合物または前記その塩を形成させることを含むプロセスによって調製される、態様６３または６４に記載のプロセス。
［態様６６］
前記式１３の化合物または前記その塩が、
式１２の化合物：
またはその塩を、４，４，５，５－テトラメチル－２－ビニル－１，３，２－ジオキサボロランと、鈴木触媒及び塩基の存在下で反応させて、前記式１３の化合物または前記その塩を形成させることを含むプロセスによって調製され、式中、Ｘ ^１ｂが、ハロである、態様６５に記載のプロセス。
［態様６７］
前記式１２の化合物または前記その塩が、
式１１の化合物：
またはその塩を塩基と反応させることを含むプロセスによって調製され、式中、Ｘ ^１ｂが、ハロである、態様６６に記載のプロセス。
［態様６８］
前記式１１の化合物または前記その塩が、
式１０の化合物：
またはその塩を２，２－ジフルオロ酢酸無水物と反応させることを含むプロセスによって調製され、式中、Ｘ ^１ｂが、ハロである、態様６７に記載のプロセス。
［態様６９］
Ｘ ^１ｂが、ブロモである、態様６６～６８のいずれか１つに記載のプロセス。
［態様７０］
（Ｒ）－１－（（７－シアノ－２－（３’－（（２－（ジフルオロメチル）－７－（（３－ヒドロキシピロリジン－１－イル）メチル）ピリド［３，２－ｄ］ピリミジン－４－イル）アミノ）－２，２’－ジメチル－［１，１’－ビフェニル］－３－イル）ベンゾ［ｄ］オキサゾール－５－イル）メチル）ピペリジン－４－カルボン酸、またはその塩を調製するプロセスであって、
（ａ）式Ａ－１ａ’の化合物：
またはその塩を、式Ａ－２ａの化合物：
またはその塩と、鈴木触媒及び塩基の存在下で反応させて、式Ａ－３ａ’の化合物：
またはその塩を形成させることと、
（ｂ）前記式Ａ－３ａ’の化合物または前記その塩を、式Ｂ－１ａの化合物：
またはその塩と、塩基の存在下で反応させて、式Ｂ－２ａ’の化合物：
またはその塩を形成させることと、
（ｃ）前記式Ｂ－２ａ’の化合物または前記その塩を、式Ｂ－３ａの塩：
と、鈴木触媒及び塩基の存在下で反応させて、式Ａ－７ａ’の化合物：
またはその塩を形成させることと、
（ｄ）前記式Ａ－７ａ’の化合物または前記その塩を脱保護して、前記（Ｒ）－１－（（７－シアノ－２－（３’－（（２－（ジフルオロメチル）－７－（（３－ヒドロキシピロリジン－１－イル）メチル）ピリド［３，２－ｄ］ピリミジン－４－イル）アミノ）－２，２’－ジメチル－［１，１’－ビフェニル］－３－イル）ベンゾ［ｄ］オキサゾール－５－イル）メチル）ピペリジン－４－カルボン酸、または前記その塩を形成させることと、を含む、前記プロセス。
［態様７１］
（ａ）式Ａ－１の化合物：
もしくはその塩（式中、Ｒ ^１は、Ｃ _１－６アルキルであり、Ｘ ^３ａは、ハロである）、または
（ｂ）式Ａ－１ａの化合物：
もしくはその塩、または
（ｃ）式Ａ－１ａ’の化合物：
もしくはその塩、または
（ｄ）式Ａ－３の化合物：
もしくはその塩（式中、Ｒ ^１は、Ｃ _１－６アルキルである）、または
（ｅ）式Ａ－３ａの化合物：
もしくはその塩、または
（ｆ）式Ａ－３ａ’の化合物：
もしくはその塩、または
（ｇ）式Ａ－４の化合物：
もしくはその塩（式中、Ｘ ^２ａは、ハロである）、または
（ｈ）式Ａ－４ａの化合物：
もしくはその塩、または
（ｉ）式Ａ－５の化合物：
もしくはその塩（式中、Ｒ ^１は、Ｃ _１－６アルキルである）、または
（ｊ）式Ａ－５ａの化合物：
もしくはその塩、または
（ｋ）式Ａ－７の化合物：
もしくはその塩（式中、Ｒ ^１は、Ｃ _１－６アルキルである）、または
（ｌ）式Ａ－７ａの化合物：
もしくはその塩、または
（ｍ）式Ａ－７ａ’の化合物：
もしくはその塩、または
（ｎ）式Ｂ－２の化合物：
もしくはその塩（式中、Ｒ ^１は、Ｃ _１－６アルキルであり、Ｘ ^１ｂは、ハロである）、または
（ｏ）式Ｂ－２ａの化合物：
もしくはその塩、または
（ｐ）式Ｂ－２ａ’の化合物：
もしくはその塩、または
（ｑ）式４の化合物：
もしくはその塩（式中、Ｘ ^３ａは、ハロである）、または
（ｒ）式５の化合物：
もしくはその塩（式中、Ｘ ^３ａは、ハロである）、または
（ｓ）式６の化合物：
もしくはその塩（式中、Ｘ ^３ａは、ハロであり、Ｒ ^１は、ｔ－ブチルである）、または
（ｔ）式４ａの化合物：
もしくはその塩、または
（ｕ）式５ａの化合物：
もしくはその塩、または
（ｖ）式６ａの化合物：
もしくはその塩、または
（ｗ）式１１の化合物：
もしくはその塩（式中、Ｘ ^３ａは、ハロである）、または
（ｘ）式１１ａの化合物：
もしくはその塩、から選択される、化合物。 In addition to those described herein, various modifications of the present invention will become apparent to those skilled in the art from the above description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, and publications cited in this application, is hereby incorporated by reference in its entirety.
The present application also includes the following aspects.
[Aspect 1]
A crystalline form of the compound of formula 1 or a pharma- ceutically acceptable salt thereof:
[Aspect 2]
The crystalline form of aspect 1, wherein said compound of formula 1 or said pharma- ceutically acceptable salt thereof is a free base of said compound of formula 1.
[Aspect 3]
The crystalline form of aspect 2, wherein the free base of the compound of formula 1 is a sesquihydrate.
[Aspect 4]
The crystalline form according to aspect 2 or 3, having Form I.
[Aspect 5]
5. The crystalline form of embodiment 4 having at least one XRPD peak selected from 7.0, 8.5, 10.0, 10.6, 14.6, 15.2, 15.8, 17.2, 20.1, 21.1, 23.9, 24.8, 26.1, 28.1, 29.6, and 30.2 degrees two theta (±0.2 degrees).
[Aspect 6]
5. The crystalline form of embodiment 4 having at least four XRPD peaks selected from 7.0, 8.5, 10.0, 10.6, 14.6, 15.2, 15.8, 17.2, 20.1, 21.1, 23.9, 24.8, 26.1, 28.1, 29.6, and 30.2 degrees two theta (±0.2 degrees).
[Aspect 7]
A crystalline form according to any one of aspects 4 to 6, having two endothermic peaks in a DSC thermogram with an onset temperature (±3°C) of 35°C and a maximum temperature (±3°C) of 68°C, and an onset temperature (±3°C) of 161°C and a maximum temperature (±3°C) of 169°C.
[Aspect 8]
The crystalline form according to aspect 2, having Form II.
[Aspect 9]
The crystalline form of aspect 8, having at least four XRPD peaks selected from 8.5, 15.0, 15.7, 17.0, 18.6, 20.2, 20.5, 21.7, 25.5, and 26.7 degrees two theta (±0.2 degrees).
[Aspect 10]
10. The crystalline form of embodiment 8 or 9, having three endothermic peaks in a DSC thermogram with a maximum temperature (±3°C) of 76°C, an onset temperature (±3°C) of 165°C and a maximum temperature (±3°C) of 173°C, an onset temperature (±3°C) of 206°C and a maximum temperature (±3°C) of 224°C.
[Aspect 11]
The crystalline form of embodiment 1, wherein said compound of formula 1 or said pharma- ceutically acceptable salt thereof is a methanesulfonate salt.
[Aspect 12]
12. The crystalline form according to aspect 11, having Form III.
[Aspect 13]
13. The crystalline form of embodiment 11 or 12, having at least four XRPD peaks selected from 5.2, 7.5, 8.2, 8.8, 9.4, 11.6, 12.4, 13.0, 14.0, 14.8, 15.8, 16.6, 16.9, 17.3, 17.9, 19.2, 23.6, 24.5, 25.5, and 26.6 degrees two theta (±0.2 degrees).
[Aspect 14]
14. The crystalline form of any one of aspects 11 to 13, having two endothermic peaks in a DSC thermogram with an onset temperature (±3°C) of 30°C and a maximum temperature (±3°C) of 67°C, and an onset temperature (±3°C) of 179°C and a maximum temperature (±3°C) of 202°C.
[Aspect 15]
1. A process for preparing (R)-1-((7-cyano-2-(3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid (compound of formula 1), or a salt thereof, comprising:
Compound of formula B-2:
or a salt thereof, with a salt of formula B-3:
(wherein M ⁺ is Li ⁺ , Na ⁺ , K ⁺ , or Cs ⁺ ) in the presence of Suzuki catalyst and base to give a compound of formula A-7:
or a salt thereof, wherein R ¹ is C _1-6 alkyl and X ^1b is halo.
[Aspect 16]
The process according to aspect 15, wherein X ^1b is bromo.
[Aspect 17]
17. The process of claim 15 or 16, wherein the Suzuki catalyst is a palladium catalyst.
[Aspect 18]
Aspect 18. The process of any one of aspects 15 to 17, wherein the base present in the reaction of the compound of formula B-2, or the salt thereof, with the salt of formula B-3 is an alkali metal carbonate.
[Aspect 19]
The process comprising:
Compound of formula B-2a:
or a salt thereof, with a salt of formula B-3a:
in the presence of Suzuki catalyst and base to give a compound of formula A-7a:
or a salt thereof.
[Aspect 20]
The process comprising:
Compound of formula B-2a':
or a salt thereof, with a salt of formula B-3a:
in the presence of Suzuki catalyst and base to give a compound of formula A-7a':
or a salt thereof.
[Aspect 21]
1. A process for preparing (R)-1-((7-cyano-2-(3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid (compound of formula 1), or a salt thereof, comprising:
Compound of formula A-3:
or a salt thereof,
or a salt thereof in the presence of a base to give a compound of formula B-2:
or a salt thereof, wherein R ¹ is C _1-6 alkyl and X ^1b and X ^2b are independently halo.
[Aspect 22]
22. The process of aspect 21, wherein the base present in the reaction of the compound of formula A-3, or the salt thereof, with the compound of formula B-1, or the salt thereof, is an alkali metal carbonate.
[Aspect 23]
23. The process according to aspect 21 or 22, wherein X ^1b is bromo or chloro.
[Aspect 24]
The process comprising:
Compound of formula B-2:
or a salt thereof, with a salt of formula B-3:
(wherein M ⁺ is Li ⁺ , Na ⁺ , K ⁺ , or Cs ⁺ ) in the presence of Suzuki catalyst and base to give a compound of formula A-7:
or a salt thereof, wherein R ¹ is C _1-6 alkyl and X ^1b is halo.
[Aspect 25]
The process comprising:
Compound of formula A-3a:
or a salt thereof,
or a salt thereof in the presence of a base to give a compound of formula B-2a:
22. The process according to aspect 21, comprising forming
[Aspect 26]
The process comprising:
Compound of formula A-3a':
or a salt thereof,
or a salt thereof in the presence of a base to give a compound of formula B-2a′:
22. The process according to aspect 21, comprising forming a compound according to claim 21, or a salt thereof.
[Aspect 27]
1. A process for preparing (R)-1-((7-cyano-2-(3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid (compound of formula 1), or a salt thereof, comprising:
Compound of formula A-3:
or a salt thereof,
or a salt thereof to give a compound of formula A-5:
or a salt thereof, wherein R ¹ is C _1-6 alkyl and X ^2a is halo.
[Aspect 28]
28. The process according to aspect 27, wherein the reacting of the compound of formula A-3, or the salt thereof, with the compound of formula A-4, or the salt thereof, is carried out in the presence of an alkali metal halide and a base.
[Aspect 29]
29. The process of claim 28, wherein the alkali metal halide is an alkali metal bromide.
[Aspect 30]
30. The process of claim 28 or 29, wherein the alkali metal halide is LiBr.
[Aspect 31]
Aspect 31. The process of any one of aspects 28 to 30, wherein the base is a tertiary amine.
[Aspect 32]
Aspect 32. The process of any one of aspects 28 to 31, wherein the base is selected from N,N-diisopropylamine, methylamine, dimethylamine, trimethylamine, and ethylamine.
[Aspect 33]
The process comprising:
Compound of formula A-3a:
or a salt thereof,
or a salt thereof in the presence of an alkali metal halide and a base to give a compound of formula A-5a:
28. The process according to aspect 27, comprising forming a compound according to claim 27, or a salt thereof.
[Aspect 34]
The process comprising:
a) Compound of formula A-3a:
or a salt thereof,
or a salt thereof in the presence of an alkali metal halide and a base to give a compound of formula A-5a:
or a salt thereof;
b) The compound of formula A-5a:
or a salt thereof,
or a salt thereof in the presence of a reducing agent to give a compound of formula A-7a:
or a salt thereof;
c) the compound of formula A-7a:
or a salt thereof with a Lewis acid to obtain a compound of formula 1:
or a salt thereof.
[Aspect 35]
1. A process for preparing (R)-1-((7-cyano-2-(3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid (compound of formula 1), or a salt thereof, comprising:
Compound of formula A-5:
or a salt thereof,
or a salt thereof in the presence of a reducing agent to give a compound of formula A-7:
or a salt thereof, wherein R ¹ is C _1-6 alkyl.
[Aspect 36]
The process comprising:
Compound of formula A-5:
or a salt thereof,
or a salt thereof in the presence of a reducing agent to give a compound of formula A-7:
or a salt thereof, wherein R ¹ is C _1-6 alkyl.
[Aspect 37]
37. The process of claim 35 or 36, wherein the reducing agent is a borohydride reducing agent.
[Aspect 38]
Aspect 38. The process of any one of aspects 35 to 37, wherein the reducing agent is selected from NaBH ₄ , NaBH ₃ CN, and NaBH(OAc) ₃ .
[Aspect 39]
Aspect 39. The process of any one of aspects 35 to 38, wherein the reacting of the compound of formula A-5, or the salt thereof, with the compound of formula A-6, or the salt thereof, is carried out in the presence of a catalyst.
[Aspect 40]
40. The process of claim 39, wherein the catalyst is trimethyl borate.
[Aspect 41]
Aspect 41. The process of any one of aspects 35 to 40, wherein the reacting of the compound of formula A-5, or the salt thereof, with the compound of formula A-6, or the salt thereof, is carried out in a solvent component comprising an organic nitrile and an organic halide.
[Aspect 42]
The process comprising:
Compound of formula A-5a:
or a salt thereof,
or a salt thereof in the presence of a reducing agent to give a compound of formula A-7a:
37. The process according to aspect 35 or 36, comprising forming
[Aspect 43]
The compound of formula A-3 or the salt thereof is
Compound of formula A-1:
or a salt thereof,
or a salt thereof in the presence of Suzuki's catalyst and a base, wherein
X ^3a is halo;
R ¹ is C _1-6 alkyl;
each R2 ^is independently selected from H and C1-6 alkyl _;
The process according to any one of aspects 21 to 24 and 27 to 32, wherein each R 2 taken together forms _{a C 2-3} alkylene ^linker _optionally substituted with 1, 2, 3, or 4 independently selected C 1-4 alkyl groups .
[Aspect 44]
The process comprising:
Compound of formula A-1a:
or a salt thereof,
or a salt thereof in the presence of a Suzuki catalyst and a base.
[Aspect 45]
The process comprising:
Compound of formula A-1a':
or a salt thereof,
or a salt thereof in the presence of a Suzuki catalyst and a base.
[Aspect 46]
The compound of formula 1 or the salt thereof is
Compound of formula A-7:
or a salt thereof,
or a salt thereof, wherein R ¹ is C _1-6 alkyl.
[Aspect 47]
Aspect 47. The process according to aspect 46, wherein said converting said compound of formula A-7, or said salt thereof, to said compound of formula 1, or said salt thereof, comprises treating said compound of formula A-7, or said salt thereof, with a Lewis acid.
[Aspect 48]
The process according to aspect 47, wherein the Lewis acid present in the conversion of the compound of formula A-7 or the salt thereof is iodotrimethylsilane.
[Aspect 49]
The process according to aspect 46, wherein said converting said compound of formula A-7, or said salt thereof, to said compound of formula 1, or said salt thereof, comprises treating said compound of formula A-7, or said salt thereof, with a base.
[Aspect 50]
Aspect 48. The process according to aspect 47, wherein the base present in the conversion of the compound of formula A-7 or the salt thereof is sodium hydroxide.
[Aspect 51]
The compound of formula 1 or the salt thereof is
Compound of formula A-7a:
or a salt thereof with a Lewis acid to obtain a compound of formula 1:
49. The process according to any one of aspects 46 to 48, wherein the compound is prepared by a process comprising forming a compound selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 2
[Aspect 52]
The compound of formula 1 or the salt thereof is
Compound of formula A-7a':
or a salt thereof with a base to form a compound of formula 1:
51. The process according to any one of aspects 46 and 49 to 50, wherein the compound is prepared by a process comprising forming a compound selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 2
[Aspect 53]
Compound of formula A-1:
or a salt thereof, comprising:
or a salt thereof under oxidative conditions to form said compound of formula A-1 or said salt thereof, wherein R ¹ is C _1-6 alkyl and X ^3a is halo.
[Aspect 54]
The compound of formula 6 or the salt thereof is
Compound of Formula 5:
or a salt thereof,
or a salt thereof, wherein R ¹ is C _1-6 alkyl and paraformaldehyde, and X ^3a is halo.
[Aspect 55]
The compound of formula 5 or the salt thereof is
Compound of Formula 4:
to said compound of formula 5 or a salt thereof, wherein X ^3a is halo.
[Aspect 56]
The compound of formula 4 is
Compound of Formula 3:
or a salt thereof,
56. The process according to aspect 55, wherein the compound is prepared by a process comprising reacting, in the presence of a base , ^with
[Aspect 57]
The compound of formula 8A is
Compound of Formula 8:
57. The process according to aspect 56, wherein the compound is prepared by a process comprising reacting X ^3a or a salt thereof with a chlorinating agent, wherein X 3a is halo.
[Aspect 58]
58. The process according to any one of aspects 53 to 57, wherein X ^3a is bromo.
[Aspect 59]
59. The process according to any one of aspects 53 to 58, wherein R ¹ is t-butyl.
[Aspect 60]
The compound of formula B-1 or the salt thereof is
Compound of formula 12:
34. The process according to any one of aspects 31 to 33, wherein the compound is prepared by a process comprising reacting X ^1b , or a salt thereof, with a halogenating agent, wherein X 1b is halo.
[Aspect 61]
The process according to aspect 60, wherein X ^1b is bromo.
[Aspect 62]
62. The process of claim 60 or 61, wherein the halogenating agent is a chlorinating agent.
[Aspect 63]
The compound of formula A-4 or the salt thereof is
Compound of formula 14:
or a salt thereof to form said compound of formula A-4, wherein X ^2a is halo.
[Aspect 64]
64. The process according to aspect 63, wherein X ^2a is chloro.
[Aspect 65]
The compound of formula 14 or the salt thereof is
Compound of formula 13:
65. The process according to aspect 63 or 64, wherein the compound is prepared by a process comprising reacting the compound of formula 14, or a salt thereof, with a halogenating agent to form said compound of formula 14 or said salt thereof.
[Aspect 66]
The compound of formula 13 or the salt thereof is
Compound of formula 12:
or a salt thereof with 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane in the presence of a Suzuki catalyst and a base to form said compound of formula 13 or said salt thereof, wherein X ^1b is halo.
[Aspect 67]
The compound of formula 12 or the salt thereof is
Compound of formula 11:
67. The process according to aspect 66, wherein the compound is prepared by a process comprising reacting X 1b with a base, or a salt thereof, wherein X ^1b is halo.
[Aspect 68]
The compound of formula 11 or the salt thereof is
Compound of formula 10:
68. The process according to aspect 67, wherein the compound is prepared by a process comprising reacting X ^1b , or a salt thereof, with 2,2-difluoroacetic anhydride, wherein X 1b is halo.
[Aspect 69]
The process according to any one of aspects 66 to 68, wherein X ^1b is bromo.
[Aspect 70]
1. A process for preparing (R)-1-((7-cyano-2-(3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid, or a salt thereof, comprising the steps of:
(a) Compound of formula A-1a′:
or a salt thereof,
or a salt thereof in the presence of Suzuki's catalyst and a base to give a compound of formula A-3a':
or a salt thereof;
(b) reacting the compound of formula A-3a′ or the salt thereof with a compound of formula B-1a:
or a salt thereof in the presence of a base to give a compound of formula B-2a′:
or a salt thereof;
(c) reacting the compound of formula B-2a′ or the salt thereof with a salt of formula B-3a:
in the presence of Suzuki catalyst and base to give a compound of formula A-7a':
or a salt thereof;
(d) deprotecting the compound of formula A-7a′ or the salt thereof to form the (R)-1-((7-cyano-2-(3′-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid, or the salt thereof.
[Aspect 71]
(a) Compound of formula A-1:
or a salt thereof, wherein R ¹ is C _1-6 alkyl and X ^3a is halo; or
(b) Compound of formula A-1a:
or its salt, or
(c) Compound of formula A-1a′:
or its salt, or
(d) Compound of formula A-3:
or a salt thereof, wherein R ¹ is C _1-6 alkyl; or
(e) Compound of formula A-3a:
or its salt, or
(f) Compound of formula A-3a′:
or its salt, or
(g) Compound of formula A-4:
or a salt thereof, wherein X2a ^is halo; or
(h) Compound of formula A-4a:
or its salt, or
(i) Compound of formula A-5:
or a salt thereof, wherein R ¹ is C _1-6 alkyl; or
(j) Compound of formula A-5a:
or its salt, or
(k) Compound of formula A-7:
or a salt thereof, wherein R ¹ is C _1-6 alkyl; or
(l) Compound of formula A-7a:
or its salt, or
(m) Compound of formula A-7a′:
or its salt, or
(n) Compound of formula B-2:
or a salt thereof, wherein R ¹ is C _1-6 alkyl and X ^1b is halo; or
(o) Compound of formula B-2a:
or its salt, or
(p) Compound of formula B-2a′:
or its salt, or
(q) A compound of formula 4:
or a salt thereof, wherein X ^3a is halo; or
(r) a compound of formula 5:
or a salt thereof, wherein X ^3a is halo; or
(s) A compound of formula 6:
or a salt thereof, wherein X ^3a is halo and R ¹ is t-butyl; or
(t) A compound of formula 4a:
or its salt, or
(u) Compound of formula 5a:
or its salt, or
(v) Compound of formula 6a:
or its salt, or
(w) a compound of formula 11:
or a salt thereof, wherein X ^3a is halo; or
(x) Compound of formula 11a:
or a salt thereof.

Claims

Formula 1:
A crystalline form of a compound represented by the formula:

The crystalline form of claim 1, wherein the compound of formula 1 or the pharma- ceutically acceptable salt thereof is a free base of the compound of formula 1.

The crystalline form of claim 2, wherein the free base of the compound of formula 1 is a sesquihydrate.

The crystalline form of claim 2 or 3 having Form I.

(a) Form I has at least one X-ray powder diffraction ( XRPD) peak selected from 7.0, 8.5, 10.0, 10.6, 14.6, 15.2, 15.8, 17.2, 20.1, 21.1, 23.9, 24.8, 26.1, 28.1, 29.6, and 30.2 degrees two-theta (±0.2 degrees ) ;
(b) Form I has at least two XRPD peaks selected from 7.0, 8.5, 10.0, 10.6, 14.6, 15.2, 15.8, 17.2, 20.1, 21.1, 23.9, 24.8, 26.1, 28.1, 29.6, and 30.2 degrees two theta (±0.2 degrees);
(c) Form I has at least three XRPD peaks selected from 7.0, 8.5, 10.0, 10.6, 14.6, 15.2, 15.8, 17.2, 20.1, 21.1, 23.9, 24.8, 26.1, 28.1, 29.6, and 30.2 degrees two theta (±0.2 degrees);
(d) Form I has at least four XRPD peaks selected from 7.0, 8.5, 10.0, 10.6, 14.6, 15.2, 15.8, 17.2, 20.1, 21.1, 23.9, 24.8, 26.1, 28.1, 29.6, and 30.2 degrees two theta (±0.2 degrees);
(e) Form I has XRPD peaks at 7.0, 8.5, 10.0, 10.6, 14.6, 15.2, 15.8, 17.2, 20.1, 21.1, 23.9, 24.8, 26.1, 28.1, 29.6, and 30.2 degrees two theta (±0.2 degrees);
(f) Form I has two endothermic peaks in a differential scanning calorimetry (DSC) thermogram with an onset temperature (±3° C.) of 35° C. and a maximum temperature (±3° C.) of 68° C., and an onset temperature (±3° C.) of 161° C. and a maximum temperature (±3° C.) of 169° C.;
(g) Form I is shown in FIG.
has an X-ray powder diffraction (XRPD) pattern as shown in
(h) Form I is shown in FIG.
has a differential scanning calorimetry (DSC) thermogram as shown in
(i) Form I is shown in FIG.
having a thermogravimetric analysis (TGA) thermogram as shown in
The crystalline form of claim 4.

The crystalline form of claim 2 having Form II.

(a) Form II has at least one XRPD peak selected from 8.5, 15.0, 15.7, 17.0, 18.6, 20.2, 20.5, 21.7, 25.5, and 26.7 degrees two theta (±0.2 degrees);
(b) Form II has at least two XRPD peaks selected from 8.5, 15.0, 15.7, 17.0, 18.6, 20.2, 20.5, 21.7, 25.5, and 26.7 degrees two theta (±0.2 degrees);
(c) Form II has at least three XRPD peaks selected from 8.5, 15.0, 15.7, 17.0, 18.6, 20.2, 20.5, 21.7, 25.5, and 26.7 degrees two theta (±0.2 degrees);
(d) Form II has at least four XRPD peaks selected from: 8.5, 15.0, 15.7, 17.0, 18.6, 20.2, 20.5, 21.7, 25.5, and 26.7 degrees two theta (±0.2 degrees);
(e) Form II has XRPD peaks at 8.5, 15.0, 15.7, 17.0, 18.6, 20.2, 20.5, 21.7, 25.5, and 26.7 degrees two theta (±0.2 degrees);
(f) Form II has three endothermic peaks in a DSC thermogram with a maximum temperature (±3° C.) of 76° C., an onset temperature (±3° C.) of 165° C. and a maximum temperature (±3° C.) of 173° C., an onset temperature (±3° C.) of 206° C. and a maximum temperature (±3° C.) of 224° C.;
(g) Form II is shown in FIG.
has an XRPD pattern as shown in
(h) Form II is shown in FIG.
Has a DSC thermogram as shown in
(i) Form II is shown in FIG.
having the TGA thermogram shown in
The crystalline form of claim 6 .

The crystalline form of claim 1, wherein the compound of formula 1 or the pharma- ceutically acceptable salt thereof is a methanesulfonate salt.

9. The crystalline form of claim 8 having Form III.

(a) Form III has at least one XRPD peak selected from 5.2, 7.5, 8.2, 8.8, 9.4, 11.6, 12.4, 13.0, 14.0, 14.8, 15.8, 16.6, 16.9, 17.3, 17.9, 19.2, 23.6, 24.5, 25.5, and 26.6 degrees two theta (±0.2 degrees);
(b) Form III has at least two XRPD peaks selected from 5.2, 7.5, 8.2, 8.8, 9.4, 11.6, 12.4, 13.0, 14.0, 14.8, 15.8, 16.6, 16.9, 17.3, 17.9, 19.2, 23.6, 24.5, 25.5, and 26.6 degrees two theta (±0.2 degrees);
(c) Form III has at least three XRPD peaks selected from 5.2, 7.5, 8.2, 8.8, 9.4, 11.6, 12.4, 13.0, 14.0, 14.8, 15.8, 16.6, 16.9, 17.3, 17.9, 19.2, 23.6, 24.5, 25.5, and 26.6 degrees two theta (±0.2 degrees);
(d) Form III has at least four XRPD peaks selected from: 5.2, 7.5, 8.2, 8.8, 9.4, 11.6, 12.4, 13.0, 14.0, 14.8, 15.8, 16.6, 16.9, 17.3, 17.9, 19.2, 23.6, 24.5, 25.5, and 26.6 degrees 2-theta (±0.2 degrees) ;
(e) Form III has XRPD peaks at 5.2, 7.5, 8.2, 8.8, 9.4, 11.6, 12.4, 13.0, 14.0, 14.8, 15.8, 16.6, 16.9, 17.3, 17.9, 19.2, 23.6, 24.5, 25.5, and 26.6 degrees two theta (±0.2 degrees);
(f) Form III has two endothermic peaks in a DSC thermogram with an onset temperature (±3° C.) of 30° C. and a maximum temperature (±3° C.) of 67° C., and an onset temperature (±3° C.) of 179° C. and a maximum temperature (±3° C.) of 202° C.;
(g) Form III is shown in FIG.
has an XRPD pattern as shown in
(h) Form III is shown in FIG.
Has the DSC thermogram shown in
(i) Form III is shown in FIG.
having the TGA thermogram shown in
10. The crystalline form of claim 8 or 9 .

11. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or excipient.

The pharmaceutical composition according to claim 11, for treating a disease or disorder associated with inhibition of PD-1/PD-L1 interaction, wherein the disease or disorder is cancer.

13. The pharmaceutical composition of claim 12, wherein the cancer is selected from lung cancer, small cell lung cancer, non-small cell lung cancer, liver cancer, hepatocellular carcinoma, melanoma, bladder cancer, urethral cancer, renal cancer, clear cell renal carcinoma, and cutaneous squamous cell carcinoma.

1. A process for preparing (R)-1-((7-cyano-2-(3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid (compound of formula 1), or a salt thereof, comprising:
Formula B- 2:
or a salt thereof ,
(wherein M ⁺ is Li ⁺ , Na ⁺ , K ⁺ , or Cs ⁺ ).
in the presence of Suzuki catalyst and base to give a compound of formula A- 7:
or a salt thereof , wherein R ¹ is C _1-6 alkyl and X ^1b is halo.

The process comprising:
Formula B-2a :
or a salt thereof ,
in the presence of Suzuki catalyst and base to give a compound of formula A-7a :
15. The process of claim 14 , comprising forming a compound of the formula:

The process comprising:
Formula B-2a ':
or a salt thereof ,
in the presence of Suzuki catalyst and base to give a compound of formula A-7a ':
15. The process of claim 14 , comprising forming a compound of the formula:

1. A process for preparing (R)-1-((7-cyano-2-(3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid (compound of formula 1), or a salt thereof, comprising the steps of:
Formula A- 3:
or a salt thereof ,
or a salt thereof in the presence of a base to obtain a compound represented by formula B- 2:
or a salt thereof , wherein R ¹ is C _1-6 alkyl, and X ^1b and X ^2b are independently halo.

The process comprising:
Formula B- 2:
or a salt thereof ,
(wherein M ⁺ is Li ⁺ , Na ⁺ , K ⁺ , or Cs ⁺ ).
in the presence of Suzuki catalyst and base to give a compound of formula A- 7:
or a salt thereof, wherein R ¹ is C _1-6 alkyl and X ^1b is halo.

The process comprising:
Formula A-3a :
or a salt thereof ,
or a salt thereof in the presence of a base to obtain a compound represented by the formula B-2a :
20. The process of claim 17 , comprising forming a compound of the formula:

The process comprising:
Formula A-3a ':
or a salt thereof ,
or a salt thereof in the presence of a base to obtain a compound represented by the formula B-2 a':
20. The process of claim 17 , comprising forming a compound of the formula:

1. A process for preparing (R)-1-((7-cyano-2-(3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid (compound of formula 1), or a salt thereof, comprising:
Formula A- 3:
or a salt thereof ,
or a salt thereof to obtain a compound represented by formula A- 5:
or a salt thereof , wherein R ¹ is C _1-6 alkyl and X ^2a is halo.

The process comprising:
Formula A-3a :
or a salt thereof ,
or a salt thereof in the presence of an alkali metal halide and a base to obtain a compound represented by the formula A-5a :
22. The process of claim 21 , comprising forming a compound of the formula:

The process comprising:
a) Formula A-3a :
or a salt thereof ,
or a salt thereof in the presence of an alkali metal halide and a base to obtain a compound represented by the formula A-5a :
or a salt thereof ;
b) The compound represented by formula A- 5a:
or a salt thereof ,
or a salt thereof in the presence of a reducing agent to obtain a compound represented by formula A-7a :
or a salt thereof ;
c) the compound represented by formula A- 7a:
or a salt thereof with a Lewis acid to obtain a compound represented by the formula 1:
or a salt thereof .

1. A process for preparing (R)-1-((7-cyano-2-(3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid (compound of formula 1), or a salt thereof, comprising:
Formula A- 5:
or a salt thereof ,
or a salt thereof in the presence of a reducing agent to obtain a compound represented by formula A- 7:
or a salt thereof , wherein R ¹ is C _1-6 alkyl.

The process comprising:
Formula A- 5:
or a salt thereof ,
or a salt thereof in the presence of a reducing agent to obtain a compound represented by formula A- 7:
or a salt thereof , wherein R ¹ is C _1-6 alkyl .

The process comprising:
Formula A-5a :
or a salt thereof ,
or a salt thereof in the presence of a reducing agent to obtain a compound represented by formula A-7a :
26. The process of claim 24 or 25 , comprising forming a compound of the formula:

The compound of formula A-3 or the salt thereof is
Formula A- 1:
or a salt thereof ,
or a salt thereof, in the presence of Suzuki catalyst and a base,
X ^3a is halo;
R ¹ is C _1-6 alkyl;
22. The process of any one of claims 17, 18 and 21, wherein each ^R2 is independently selected from H and _C1-6 alkyl, or each ^R2 together form a _C2-3 alkylene linker optionally substituted with 1 , 2, 3 , or 4 independently selected _C1-4 alkyl groups.

The process comprising:
Formula A-1a :
or a salt thereof ,
or a salt thereof in the presence of Suzuki catalyst and a base .

The process comprising:
Formula A- 1a':
or a salt thereof ,
or a salt thereof in the presence of Suzuki catalyst and a base .

The compound of formula 1 or the salt thereof is
Formula A- 7:
or a salt thereof ,
or a salt thereof, wherein R ¹ is C _1-6 alkyl.

The compound of formula 1 or the salt thereof is
Formula A-7a :
or a salt thereof with a Lewis acid to obtain a compound represented by the formula 1:
31. The process of claim 30 , wherein the compound is prepared by a process comprising forming a compound of the formula:

The compound of formula 1 or the salt thereof is
Formula A-7a ':
or a salt thereof with a base to obtain a compound represented by the formula 1:
31. The process of claim 30 , wherein the compound is prepared by a process comprising forming a compound of the formula:

Formula A- 1:
or a salt thereof, comprising a compound of formula 6:
or a salt thereof under oxidative conditions to form said compound of formula A-1 or said salt thereof, wherein R ¹ is C _1-6 alkyl and X ^3a is halo.

The compound of formula 6 or the salt thereof is
Formula 5:
or a salt thereof ,
or a salt thereof, wherein R ¹ is C _1-6 alkyl and paraformaldehyde, and X ^3a is halo .

The compound of formula 5 or the salt thereof is
Formula 4:
^35. The process of claim 34 , wherein the compound is prepared by a process comprising hydrolyzing a compound of the formula:

The compound of formula 4 is
Formula 3:
or a salt thereof ,
^36. The process of claim 35 , wherein the compound is prepared by a process comprising reacting, in the presence of a base, a compound of the formula:

The compound of formula 8A is
Equation 8:
or a salt thereof, with a chlorinating agent, wherein X ^3a is halo .

The compound of formula B-1 or the salt thereof is
Formula 12:
or a salt thereof, with a halogenating agent, wherein X ^1b is halo.

The compound of formula A-4 or the salt thereof is
Formula 14:
or a salt thereof to form said compound of formula A- 4 , wherein X ^2a is halo.

The compound of formula 14 or the salt thereof is
Formula 13 :
or a salt thereof with a halogenating agent to form said compound of formula 14 or said salt thereof.

The compound of formula 13 or the salt thereof is
Formula 12:
or a salt thereof with 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane in the presence of a Suzuki catalyst and a base to form said compound of formula 13 or said salt thereof, wherein X ^1b is halo.

The compound of formula 12 or the salt thereof is
Formula 1 1:
or a salt thereof, with a base, wherein X ^1b is halo .

The compound of formula 11 or the salt thereof is
Formula 10 :
or a salt thereof with 2,2 - difluoroacetic anhydride, wherein X ^1b is halo.

1. A process for preparing (R)-1-((7-cyano-2-(3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid, or a salt thereof, comprising the steps of:
(a) Formula A-1 a':
or a salt thereof ,
or a salt thereof in the presence of Suzuki catalyst and a base to obtain a compound of formula A-3 a':
or a salt thereof ;
(b) reacting a compound of formula A-3a′ or a salt thereof with a compound of formula B-1a :
or a salt thereof in the presence of a base to obtain a compound represented by the formula B-2 a':
or a salt thereof ;
(c) reacting the compound of formula B-2a′ or the salt thereof with a compound of formula B-3a :
in the presence of Suzuki catalyst and base to give a compound of formula A-7a ':
or a salt thereof ;
(d) deprotecting the compound of formula A-7a′ or the salt thereof to form the (R)-1-((7-cyano-2-(3′-((2-(difluoromethyl)-7-((3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-4-carboxylic acid, or the salt thereof.

(a) Formula A- 1:
or a salt thereof (wherein R ¹ is C _1-6 alkyl and X ^3a is halo); or (b) a compound represented by formula A-1a :
or a salt thereof, or (c) a compound represented by formula A-1 a′:
or a salt thereof, or (d) a compound represented by formula A- 3:
or a salt thereof (wherein R ¹ is C _1-6 alkyl); or (e) a compound represented by formula A-3a :
or a salt thereof, or (f) a compound represented by formula A-3 a′:
or a salt thereof, or (g) a compound represented by formula A- 4:
or a salt thereof (wherein ^X2a is halo); or (h) a compound represented by formula A-4a :
or a salt thereof, or (i) a compound represented by formula A- 5:
or a salt thereof (wherein R ¹ is C _1-6 alkyl); or (j) a compound represented by formula A-5a :
or a salt thereof, or (k) a compound represented by formula A- 7:
or a salt thereof (wherein R ¹ is C _1-6 alkyl); or (l) a compound represented by formula A-7a :
or a salt thereof, or (m) a compound represented by formula A-7 a′:
or a salt thereof, or (n) a compound represented by formula B- 2:
or a salt thereof (wherein R ¹ is C _1-6 alkyl and X ^1b is halo); or (o) a compound represented by formula B-2a :
or a salt thereof, or (p) a compound represented by formula B-2 a′:
or a salt thereof, or (q) a compound represented by formula 4:
or a salt thereof (wherein X ^3a is halo); or (r) a compound of formula 5:
or a salt thereof (wherein X ^3a is halo); or (s) a compound of formula 6:
or a salt thereof (wherein X ^3a is halo and R ¹ is t-butyl); or (t) a compound represented by formula 4a :
or a salt thereof, or (u) a compound represented by formula 5a :
or a salt thereof, or (v) a compound represented by formula 6a :
or a salt thereof, or (w) a compound represented by formula 11:
or a salt thereof (wherein ^X3a is halo); or (x) a compound of formula 11a :
or a salt thereof ,
A compound selected from: