What is the meaning of "be'Yad Ramah"?
Rashi and Targum Yonasan: It means 'on purpose', literally 'highhandedly' (and he did not do Teshuvah - Targum Yonasan).
Sanhedrin, 99b: It means someone who presents his own (unfounded) interpretations of the Torah - like Menasheh ha'Melech. 1
Sanhedrin, Ibid.: About whom the Navi writes in Yeshayah, 5:18 "Hoy Moshchei Avon be'Havlei Shav'. Refer also to 15:31:1:5.
What is the meaning of "es Hashem Hu Megadef'"?
Rashi: It means that he blasphemes 1 Hashem, 2 and the Gemara in Kerisos 7b learns that someone who blasphemes Hashem is Chayav Kareis.
Rashbam: It means that he worships Avodah-Zarah.
Targum Yonasan: It means that he angers Hashem.
Rashi: As in Yechezkel, 5:15 and in Yeshayah. See Torah Temimah, citing Kerisos, 7b, and note 83, who discusses the various opinions at length.
What are the implications of "Es Hashem hu Megadef"?
Seforno: It implies that, on account of the Chilul Hashem, even Teshuvah - out of fear of the punishment - will not atone for him until he dies. 1
Seforno: Which explains why the Teshuvah following the episode of the spies was not accepted, as the Torah writes in Devarim, 1:45.